Skip to main content
NCBI home page
Frontiers in Pharmacology logoLink to Frontiers in Pharmacology
. 2026 Sep 11;17:1924049. doi: 10.3389/fphar.2026.1924049

15- Deoxy-Δ12,14-prostaglandin J2 upregulates COX-2 expression and PGE2 in mouse mesangial cells through a mechanism independent of PPARγ

Bo Yu 1, Yuping Zhang 1, Zhenqi Hu 1, Xuyan Fu 1, Xinyi Shen 1, Xinghao Rong 1, Guangrui Yang 2,*
PMCID: PMC13612431  PMID: 42798459

Abstract

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous cyclooxygenase-derived lipid mediator and natural ligand of peroxisome proliferator-activated receptor gamma (PPARγ), plays important roles in inflammatory regulation and renal pathophysiology. However, the effect of 15d-PGJ2 on cyclooxygenase-2 (COX-2) expression in mesangial cells and the involvement of PPARγ in this process remain unclear. In this study, we investigated the regulation of COX-2 expression and prostaglandin E2 (PGE2) production by 15d-PGJ2 in primary cultured mouse mesangial cells and determined the role of PPARγ using pharmacological and genetic approaches. Treatment with 15d-PGJ2 significantly increased COX-2 mRNA and protein expression, accompanied by a marked elevation of PGE2 production. Pharmacological inhibition of PPARγ using the selective antagonist GW9662 did not affect 15d-PGJ2-induced COX-2 expression or PGE2 production. Similarly, overexpression of dominant-negative PPARγ, siRNA-mediated knockdown, and Cre-mediated genetic deletion of PPARγ failed to attenuate the induction of COX-2 by 15d-PGJ2. Functional reporter assays confirmed effective modulation of PPARγ transcriptional activity under these conditions, indicating that the lack of effect was not due to insufficient inhibition. These findings demonstrate that 15d-PGJ2 induces COX-2 expression and enhances PGE2 production in mouse mesangial cells via a mechanism independent of PPARγ. This PPARγ-independent action suggests alternative signaling pathways through which endogenous lipid mediators regulate inflammatory responses in the kidney. Our results provide new insight into the complex role of prostaglandin metabolites in renal inflammatory signaling and highlight the importance of receptor-independent actions of electrophilic lipid mediators.

Keywords: 15-deoxy-δ12, 14-prostaglandin J2, cyclooxygenase-2, glomerular, mesangial cells, PPARγ, prostaglandin E2

1. Introduction

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear transcription factor belonging to the nuclear hormone receptor superfamily. PPARγ binds, as a heterodimer with retinoid X receptor (RXR) (Fang et al., 2021), to peroxisome-proliferator response element (PPRE) located in the promoters of numerous target genes that are involved in various physiological or pathophysiological processes including metabolism, inflammation, oxidative stress, tumor and development (Thakur et al., 2023; Chen et al., 2023; Hernandez-Quiles et al., 2021; Guan, 2004; Colca et al., 2014; Zhou et al., 2020). It is well established that PPARγ is constitutively expressed in glomerular mesangial cells and plays protective roles in the progression of nephropathy (Agrawal et al., 2021; Kökény et al., 2020). Agonists of PPARγ include synthetic compounds such as antidiabetic thiazolidinediones, and natural ligands such as prostaglandin D2 (PGD2) metabolite 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) (Guan and Breyer, 2001). The endogenous ligand, 15d-PGJ2, was shown initially to have a major function in adipocyte differentiation and glucose homeostasis (Chawla et al., 1994; Tontonoz et al., 1994), and has been reported to reverse the phenotypic changes of mesangial cells and regulate cell proliferation and death (Rovin et al., 2002; Asano et al., 2000; Stamatakis et al., 2006).

Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis, catalyzing the conversion of arachidonic acid to PGH2, a common precursor for bioactive prostaglandins including PGJ2 (Wang et al., 2018). Among its two major isoforms, COX-1 is constitutively expressed to maintain physiological PG functions, while COX-2 is an immediate-early response gene rapidly induced during inflammatory disorders and oxidative stress (Grosser et al., 2010). Previous studies indicate that PPARγ ligands can suppress COX-2 expression in various cell types, such as epithelial cells (Scoditti et al., 2010), synoviocytes (Tsubouchi et al., 2001), monocytes (Pontsler et al., 2002), and macrophage-like differentiated cells (Inoue et al., 2000). Conversely, induction of COX-2 by these ligands has also been reported in epithelial cells and synovial fibroblasts (Kalajdzic et al., 2002). Studies utilizing the irreversible PPARγ-selective antagonist GW9662 and dominant-negative constructs suggest that this regulation is highly cell-type-specific and involves both PPARγ dependent and independent mechanisms (Scoditti et al., 2010; Konger et al., 2010; Ayoub et al., 2009).

In this context, cyclopentenone prostaglandins like 15d-PGJ2 are increasingly recognized not merely as classical PPARγ ligands, but as specialized bioactive lipid mediators that actively modulate inflammation and promote tissue homeostasis (Macia Guardado et al., 2025; Park, 2026; Peh and Chen, 2025). Recent evidence highlights that such lipid mediators can regulate inflammatory gene expression through diverse signaling pathways beyond classical nuclear receptor activation (Li et al., 2023; Hinz et al., 2003; Bianchi et al., 2005; Lee et al., 2007). In glomerular pathophysiology—such as in diabetic nephropathy, lupus nephritis, and IgA nephropathy—the COX-2-derived PGE2 pathway plays a pivotal role in driving mesangial expansion and inflammatory progression. Although synthetic PPARγ agonists (e.g., pioglitazone) and 15d-PGJ2 have been explored in animal models of nephropathy, the double-edged sword nature of 15d-PGJ2 remains a challenge. Crucially, 15d-PGJ2 exhibits a unique concentration-dependent bimodal activity: acting as a potent PPARγ agonist at low (nanomolar) concentrations, while imposing receptor-independent electrophilic stress at higher (micromolar) concentrations. However, the precise role of PPARγ in mediating 15d-PGJ2-induced COX-2 expression in mesangial cells remains incompletely understood.

Therefore, we hypothesized that at micromolar concentrations, 15d-PGJ2 upregulates COX-2 and PGE2 in mouse mesangial cells through its electrophilic α, β-unsaturated carbonyl moiety rather than through canonical PPARγ activation, and that this effect would consequently be resistant to PPARγ antagonism, dominant-negative interference, siRNA knockdown, and genetic deletion. Using complementary pharmacological inhibition, dominant-negative interference, siRNA-mediated knockdown, and genetic deletion approaches, we demonstrate that 15d-PGJ2 induces COX-2 expression and PGE2 production through a PPARγ-independent mechanism. These findings provide new insight into receptor-independent signaling pathways of endogenous prostaglandin metabolites in renal cells.

2. Materials and methods

2.1. Chemicals and reagents

15d-PGJ2, GW9662 and Rabbit anti-human COX-2 antibody were obtained from Cayman Chemical Company (Ann Arbor, MI). Mouse anti-human PPARγ and α-tubulin antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA) and Sigma (St. Louis, MO), respectively. All the corresponding secondary antibodies and other reagents for Western blotting were from Zhongshan Golden Bridge Company (Beijing, China). Real-time PCR was performed in PTC-200 (MJ Research, Waltham, MA) with reagents obtained from Tiangen (Beijing, China). The wild-type and dominant negative PPARγ plasmid, PPRE luciferase plasmids and the Cre adenovirus were kindly provided by Dr. Youfei Guan (Dalian Medical University, China). The PPARγ siRNA was constructed by Kangcheng Company (Shanghai, China).

2.2. Primary culture of mouse mesangial cells

3-week-old PPARγflox/flox (PPARγf/f) mice and C57BL/6 mice were used for primary mesangial cell culture as previously described with modifications (Wu et al., 2004). Briefly, renal cortex was minced and incubated in a 50 mL-tube containing 5 mL of 1 mg/mL Collagenase II in PBS at 37 °C. After 1-h gentle shaking, the digested cortexes were poured in a 40 µm sieve and smashed, followed by two washes using 20 mL of PBS. Then invert the sieve and set it on a culture dish and wash the sieve again. The flow through containing glomeruli was collected and centrifuged at 1000 rpm for 10 min. Discard The supernatant was discarded, and the cell pellet was harvested in DMEM containing 20% FBS, streptomycin (100 mg/mL) and penicillin (100units/mL). Cells were grown at 37 °C in a humidified atmosphere of 95% air/5% CO2. The cells were left undisturbed for 5 days, and the culture medium was exchanged every 2 days thereafter.

Before experiments, cells were seeded into 6-well plates at 1 × 105/well. After confluence, the medium was exchanged with serum-free medium for 24 h to maintain the cells in a quiescent, non-catabolic state for extended time periods in the subsequent experiments. Then, the cells were treated with 10 μM GW9662 for 1 h prior to the addition of 10 μM 15d-PGJ2 for indicated time. To construct a PPARγ knockout cell line, the mesangial cells from PPARγf/f mice were infected with adenovirus expressing Cre recombinase (Cre-Ad) at a multiplicity of infection (MOI) of 100 as determined with an adenovirus expressing GFP (GFP-Ad). Two days after infection, fresh growth media was changed for the successive 15d-PGJ2 treatment.

2.3. Reverse transcription PCR (RT-PCR)

Total RNA was extracted from cultured mesangial cell using RNAtrip Reagent (Applygen, China). 2 μg total RNA were reverse transcribed to cDNA using hexadeoxynucleotide random primers and Moloney murine leukemia virus reverse transcriptase (Promega, Madison, WI) according to manufacturer’s instructions. The cDNAs were used as templates for RT-PCR and quantitative RT-PCR. The primer sets for COX-2 (cyclooxygenase-2) are 5′-AGA​AGG​AAA​TGG​CTG​CAG​AA-3’ (sense) and 5′- GCT​CGG​CTT​CCA​GTA​TTG​AG-3’ (antisense), for PPARγ (peroxisome proliferator-activated receptor gamma) 5′-GTTTGCTGTGAA GTTCAATGC-3’ (sense) and 5′-GTC​TGT​CTC​CGT​CTT​CTT​GAT-3’ (antisense), and for α-tubulin (alpha-tubulin) 5′-AGC​CAT​GTA​CGT​AGC​CAT​CC-3’ (sense) and 5′-GCTGTGGTG GTGAAGCTGTA-3’ (antisense). The PCR reactions were carried out at 94 °C for 5 min, followed by 35 cycles of 94 °C for 30 s, 60 °C for 30 s, and 72 °C for 30 s with a final extension at 72 °C for 5 min.

2.4. Western blot analysis

Cellular proteins were extracted as previously (Yang et al., 2006). Proteins were separated by SDS-PAGE and transferred to nitrocellulose. Immunoblotting was performed using antibodies directed against PPARγ, COX-2, and α-tubulin in 1 × PBS containing 0.05% (v/v) Tween-20% and 5% (w/v) BSA. After incubation in horseradish peroxidase-conjugated secondary antibodies, the blots were washed and applied to enhanced chemiluminescent detection reagent. The signals were revealed using Kodak film and quantified by densitometry.

2.5. Prostaglandin E2 enzyme immunoassay

Cells were plated in six-well plates, following treatments, the harvested supernatants were centrifuged to remove particulate matters and assayed for PGE content by a PGE-specific EIA kit following the manufacturer’s instruction (Cayman Chemical, Ann Arbor, MI).

2.6. PPRE reporter assay

Transient transfection was performed in cultured mesangial cells using High Efficient Transfection Reagent (Invitrogen, Carlsbad, CA). Cells were transfected with a wild-type PPARγ construct or a dominant-negative PPARγ construct, together with a PPRE-luciferase reporter plasmid and a β-galactosidase vector. An empty vector pcDNA3.1 was used as an internal control. PPRE luciferase was measured 24 h after transfection. β-galactosidase activity was measured for normalization.

2.7. siRNA transfection

We selected siRNA corresponding to a conserved sequence (nucleotides 545–563; Accession No. NM_011146) to target transcript of the mouse PPARγ gene. We also used a scramble siRNA whose sequence did not match any mouse genomic sequence. Transfection of siRNA was performed on mouse mesangial cells at 60%–70% confluence. 2 μL of High Efficient Transfection Reagent (Invitrogen, Carlsbad, CA) was mixed with 100 uL of Opti-MEM medium (Invitrogen Carlsbad, CA) and incubated for 5 min at room temperature. 5 μg siRNA plasmid were diluted in another 100 uL of Opti-MEM medium, mixed with the diluted transfection reagents and incubated for another 15 min, then the mixture was added to the cells (2 mL of DMEM medium with 5% FBS) and lasted for transfection. Scramble siRNA controls were used in parallel. After 48 h incubation, the activity of GFP was measured to evaluate transfection efficiency, and then cells were treated with or without 15d-PGJ2 for another 4 h before lysis.

2.8. Statistical analysis

All data are presented as mean ± SEM. Statistical analyses were performed using Student’s t-test or one-way analysis of variance (ANOVA) where appropriate. Differences were considered statistically significant at P < 0.05.

3. Results

3.1. 15d-PGJ2 induces COX-2 expression and PGE2 production in mouse mesangial cells

We treated primary cultured mouse mesangial cells with 10 uM 15d-PGJ2 for 4 h and found that both mRNA and protein level of COX-2 were increased (Figures 1a,b). To determine whether the 15d-PGJ2 induced COX-2 is functional, we measured the levels of PGE2, one of major products of COX-2, in the culture medium. As the data shown, 15d-PGJ2 treatment resulted in a four-fold increase in PGE2 production (Figure 1c).

FIGURE 1.

Figure composed of three panels showing the effect of 15d-PGJ2 treatment compared to control. Panel a, bar graph indicates increased COX-2 mRNA levels in the 15d-PGJ2 group. Panel b, immunoblot and corresponding bar graph show upregulation of COX-2 protein and normalization to α-tubulin. Panel c, bar graph displays elevated PGE2 levels after 15d-PGJ2 treatment. Error bars and asterisks denote statistical significance.

Open in a new tab

15d-PGJ2 upregulates mRNA (a) and protein (b) expression of COX-2 and increases PGE2 production (c) in mouse mesangial cells (*p < 0.05 versus control, n = 3).

3.2. Induction of COX-2 by 15d-PGJ2 cannot be blocked by PPARγ antagonist GW9662

15d-PGJ2 has been identified as a natural ligand for PPARγ. In order to determine whether the induction of COX-2 by 15d-PGJ2 is PPARγ-dependent, we first examined the expression of PPARγ in the mesangial cells. As shown in Figure 2a, PPARγ mRNA was detected by RT-PCR, yielding an expected 277 bp fragment in three preparations of mesangial cells. Western blot analysis showed that PPARγ protein was also constitutively expressed in mesangial cells (Figure 2b). Next, we investigated whether the induction of COX-2 by 15d-PGJ2 can be blocked by PPARγ antagonist GW9662. As shown in Figures 2c,d, GW9662 was not able to inhibit 15d-PGJ2-induced COX-2 protein expression or PGE2 production.

FIGURE 2.

Panel a shows gel electrophoresis bands for PPARγ and α-tubulin genes with respective base pair sizes. Panel b displays Western blot bands for PPARγ and GAPDH proteins. Panel c includes Western blot bands for COX-2 and α-tubulin, and a bar graph depicting relative protein levels under different conditions, with asterisks indicating statistical significance. Panel d contains a bar graph presenting PGE₂ concentration with treatment conditions labeled below, and asterisks showing significant differences.

Open in a new tab

PPARγ antagonist GW9662 has no effect on the induction of 15d-PGJ2 on COX-2 expression and PGE2 production. (a) PPARγ mRNA constitutively expressed in cultured mouse mesangial cells. (b) PPARγ protein constitutively expressed in cultured mouse mesangial cells. (c) PPARγ antagonist GW9662 has no effect on 15d-PGJ2-induced COX-2 protein expression (*p < 0.05; ***p < 0.001 versus control, n = 3). (d) PPARγ antagonist GW9662 has no effect on 15d-PGJ2-induced PGE2 production (*p < 0.05 versus control, n = 3).

3.3. PPARγ dominant negative cannot reverse the induction of COX-2 by 15d-PGJ2

To provide further evidence, we transfected the cells with plasmids expressing wild-type PPARγ (WT-PPARγ) or dominant negative PPARγ (D/N-PPARγ). This D/N-PPARγ harbors two mutations in trans-activation domain and is a potent inhibitor of PPARγ function. As shown in Figure 3a, the WT-PPARγ significantly increased the PPRE luciferase activity, while the D/N-PPARγ plasmid decreased the PPRE activity. Furthermore, as expected, neither wild-type nor dominant negative plasmid has effect on 15d-PGJ2-induced COX-2 expression (Figure 3b) and PGE2 production (Figure 3c).

FIGURE 3.

Panel a displays a bar graph showing increased PPRE luciferase activity in WT-PPAR compared to pcDNA3.1 control and significantly decreased activity in D/N-PPAR. Panel b contains Western blots for COX-2 and α-tubulin, showing varying COX-2 expression across conditions with corresponding loading controls, and a legend indicating plasmid and treatment combinations. Panel c presents a bar graph indicating higher PGE2 concentration in 15d-PGJ2 treated groups compared to controls for all constructs, with statistical significance marked.

Open in a new tab

PPARγ dominant negative has no effect on the induction of 15d-PGJ2 on COX-2 expression and PGE2 production. (a) WT-PPARγ increases while D/N-PPARγ decreases PPRE luciferase activity; (*p < 0.05; **p < 0.01 versus control; #p < 0.05, versus WT-PPARγ, n = 3). (b) Neither WT-PPARγ nor D/N-PPARγ has effect on 15d-PGJ2-induced COX-2 protein expression. (c) Neither WT-PPARγ nor D/N-PPARγ has effect on 15d-PGJ2-induced PGE2 production (*p < 0.05 versus control, n = 3).

3.4. PPARγ siRNA failed to reverse the induction of COX-2 by 15d-PGJ2

We co-transfected a PPARγ siRNA plasmid and a GFP expression plasmid to the mesangial cells. Transfection efficiency was validated by the ratio of GFP positive cells. About 90% cells were transfected as shown in Figure 4a. Meanwhile both RNA (Figure 4b) and protein levels (Figure 4c) of PPARγ were significantly reduced by siRNA transfection. While this reduction failed to affect the induction of 15d-PGJ2 on COX-2 expression in either mRNA (Figure 4d) or protein (Figure 4e) level.

FIGURE 4.

Figure with five panels showing experimental results on the effect of PPARγ knockdown and 15d-PGJ2 on COX-2 expression. Panel (a) is a fluorescence microscopy image of cells stained in green with an inset showing a brightfield image. Panel (b) displays gel bands for semi-quantitative RT-PCR of PPARγ and α-tubulin in negative vector and PPARγ-siRNA treated groups. Panel (c) shows a Western blot of PPARγ in negative vector and PPARγ-siRNA conditions. Panel (d) presents a bar graph of relative COX-2 mRNA levels under different treatments, highlighting significant increases after 15d-PGJ2 stimulation and siRNA knockdown. Panel (e) includes Western blot images for COX-2 and α-tubulin with a corresponding bar graph for relative COX-2 protein levels, indicating higher expression with 15d-PGJ2 and siRNA treatment.

Open in a new tab

PPARγ siRNA has no effect on the induction of 15d-PGJ2 on COX-2 expression. (a) Transfection efficiency evaluated by GFP-positive cells (green fluorescence; inset: bright-field image; scale bar = 100 μm). Quantitative analysis of GFP-positive cells from multiple randomly selected fields indicated approximately 90% transfection efficiency. (b) PPARγ mRNA expression was decreased by PPARγ siRNA transfection. (c) PPARγ protein expression was inhibited by PPARγ siRNA transfection. (d) PPARγ siRNA has no effect on 15d-PGJ2-induced COX-2 mRNA expression. (*p < 0.05 versus negative vector only; #p < 0.05, versus PPARγ-siRNA only, n = 3) (e) PPARγ siRNA has no effect on 15d-PGJ2-induced COX-2 protein expression (*p < 0.05 versus negative vector only; #p < 0.05, versus PPARγ-siRNA only, n = 3).

3.5. PPARγ gene knockout failed to abolish the induction of 15-dPGJ2 on COX-2 expression and PGE2 production

Finally, we knocked out the PPARγ gene in the mesangial cells. Mesangial cells cultured from PPARγf/f mice were infected with Cre-expressing adenovirus (Cre-Ad). The adenovirus expressing GFP protein (GFP-Ad) was used as control. Cre-Ad infection dramatically decreased PPARγ expression in both mRNA and protein levels (Figures 5a,b). While 15d-PGJ2 induced COX-2 expression (Figure 5c) and PGE2 production (Figure 5d) remained comparable to that in GFP-Ad infected cells and Cre-Ad infected cells.

FIGURE 5.

Panel a shows gel electrophoresis bands indicating decreased PPARγ expression in Cre compared to GFP, with tubulin as a loading control. Panel b is a bar graph showing reduced relative PPARγ protein level in Cre versus GFP, with asterisks marking significant reduction. Panel c includes a western blot and quantification bar graph displaying increased COX-2 levels in GFP-15d and Cre-15d, normalized to α-tubulin, with statistical markers for significance. Panel d is a bar chart showing higher PGE₂ levels in GFP-15d and Cre-15d groups, marked with asterisks and hash symbols for statistical significance.

Open in a new tab

PPARγ gene knockout has no effect on the induction of 15d-PGJ2 on COX-2 expression and PGE2 production. (a) PPARγ mRNA expression was blocked by Cre adenovirus infection. (b) PPARγ protein expression was inhibited by Cre adenovirus infection. (c) Cre-mediated PPARγ deletion has no effect on 15d-PGJ2-induced COX-2 protein expression (*p < 0.05 versus GFP-ctrl; #p < 0.05, versus Cre-ctrl, n = 3). (d) Cre-mediated PPARγ deletion has no effect 15d-PGJ2-induced PGE2 production (*p < 0.05 versus GFP-ctrl; #p < 0.05, versus Cre-ctrl, n = 3).

4. Discussion

Accumulating evidence suggests that cyclooxygenase (COX)-2 derived prostaglandin E2 (PGE2) participates in many renal pathological processes such as glomerulosclerosis (Komers and Epstein, 2002; Zhuang et al., 2018; Nguyen, 2006). The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to play a protective role in progression of nephropathy (Wu et al., 2009; Zhang et al., 2020). 15d-PGJ2, an endogenous PPARγ ligand, also a COX metabolite, has been considered as a potent negative regulator of inflammatory responses and oxidative stress and a promising therapeutic agent of many inflammatory diseases (Bie et al., 2018; Liu et al., 2012). However, the pharmacological effect of 15d-PGJ2 on the expression of COX-2 and the consequent PGE2 production remains under debate. It is increasingly recognized that many PPARγ ligands can exert biological effects through both receptor-dependent and receptor-independent mechanisms, and that “PPARγ ligand” is not synonymous with “PPARγ-dependent effect” (Chang et al., 2025).

It was reported that 15d-PGJ2 inhibits cytokine-elicited PGE2 synthesis and COX-2 expression in many cell types, such as macrophages (Inoue et al., 2000), synovial fibroblasts (Tsubouchi et al., 2001), and rat mesangial cells (Sawano et al., 2002; Sánchez-Gómez et al., 2004). However, others showed that in contrast 15d-PGJ2 augments COX-2 expression and PGE2 synthesis in human osteoarthritic chondrocytes (Fahmi et al., 2002). Furthermore, in human mesangial cells, 15d-PGJ2 was reported to upregulate COX-2, while this upregulation of COX-2 did not result in increased PGE2 production (Reyes-Martin et al., 2008). While different cellular sources or species disparities may contribute to these discrepancies, a critical distinction likely lies in the preexisting cellular state. Previous studies often evaluated 15d-PGJ2 in the context of active inflammation (e.g., cytokine pre-stimulation), whereas our study investigated its direct effects on quiescent, unstimulated cells. In the present study, using cultured mouse glomerular mesangial cells, we found that 15d-PGJ2 can dramatically upregulate COX-2 expression at both mRNA and protein levels in mouse mesangial cells. Also, the PGE2 production was increased after 15d-PGJ2 treatment. Accumulating evidence from studies of patients, animal models, or cell models has shown that COX-2-derived PGE2 in the kidney is involved in the pathophysiological processes of various renal diseases, such as glomerulonephritis, interstitial nephritis, and renal cell carcinoma (Kömhoff et al., 2000; Reichman et al., 2001; Hirasawa et al., 2006; Chen et al., 2004; Yang et al., 2015). Our findings that 15d-PGJ2 increases COX-2 expression and PGE2 production in mouse mesangial cells emphasize the necessity of re-evaluation of the potency of 15d-PGJ2 in the treatment of renal glomerular diseases.

Regarding the underlying signaling mechanisms, our data provide compelling evidence that this induction is PPARγ-independent. Specifically (Fang et al., 2021): The selective PPARγ antagonist GW9662 (Thakur et al., 2023); PPARγ dominant negative construct (Chen et al., 2023); PPARγ siRNA; and (Hernandez-Quiles et al., 2021) PPARγ loss-of-function had no effect on 15d-PGJ2 induced COX-2 expression and PGE2 production. There is evidence that several intracellular signaling molecules, such as PI3K, NF-κB, activator protein 1 (AP-1), may contribute to the PPARγ-independent effects (Sawano et al., 2002; Takeda et al., 2001; Patel et al., 2005; Pereira et al., 2006; Bianchi et al., 2014). Studies also showed that 15d-PGJ2 induced a variety of cellular responses including activation of MAPKs (Kim J. et al., 2008; Lim et al., 2007), inactivation of p53 (Straus and Glass, 2007) and modulation of COX-2 (Kim E. et al., 2008) via PPARγ-independent mechanisms. The PPARγ-independent induction of COX-2 observed in our study likely stems from the unique chemical properties of 15d-PGJ2. Unlike synthetic thiazolidinediones, 15d-PGJ2 possesses a reactive α, β-unsaturated carbonyl moiety within its cyclopentenone ring. This structural feature renders it highly electrophilic, enabling the formation of covalent adducts with nucleophilic cysteine residues of cellular proteins via Michael addition (Tontonoz et al., 1994; Nguyen, 2006).

We postulate that at micromolar concentrations, 15d-PGJ2 imposes “electrophilic stress” on mesangial cells, potentially by depleting intracellular glutathione (GSH) or directly modifying redox-sensitive signaling molecules (such as Keap1 or IKK kinases). This is consistent with previous findings that 15d-PGJ2 upregulates COX-2 via a thiol-sensitive mechanism (Zhang et al., 2020) and involves reactive oxygen species (ROS) generation (Kitz et al., 2011). However, direct measurements of GSH levels and ROS production in our mesangial cell system were not performed in the current study, and thus this proposed mechanism remains to be experimentally validated in our experimental context. It is also worth noting that the 10 μM concentration of 15d-PGJ2 used in this study, while higher than physiological circulating levels, is consistent with concentrations commonly employed in mechanistic studies of 15d-PGJ2 in mesangial cells. Sawano et al. (2002) demonstrated PPARγ-independent inhibition of IL-1β-induced COX-2 expression using 10 μM 15d-PGJ2 in rat mesangial cells (Sawano et al., 2002), and Reyes-Martin et al. (2008) showed that 10 μM 15d-PGJ2 upregulates COX-2 expression in human mesangial cells through a thiol-sensitive mechanism (Reyes-Martin et al., 2008). Thus, the concentration used in our study is appropriate for investigating the mechanistic question of PPARγ dependence, which was the primary objective of this work. However, we acknowledge that whether lower, nanomolar concentrations (e.g., 0.1–1 μM) induce COX-2 remains an open question for future study.

This chemical reactivity operates distinctly from the classical ligand-receptor interaction, thereby explaining why genetic ablation or pharmacological blockade of PPARγ failed to abrogate COX-2 upregulation. The concept of “metabolic reprogramming”—whereby a pathological stimulus fundamentally reshapes cellular metabolic pathways—has emerged as a key framework for understanding how lipid mediators influence cellular function (Wang et al., 2026). Given this unique mode of action, this electrophilic stress may converge on multiple intracellular signaling hubs to drive COX-2 transcription. For instance, redox imbalance could modulate the lipid phosphatase PTEN, thereby relieving its brake on the PI3K/Akt axis, a pathway known to promote COX-2 expression (Takeda et al., 2001; Kim E. et al., 2008; An et al., 2022). Downstream of such kinase cascades, the activation of transcription factors like STAT6 (Jiao et al., 2021a; Jiao et al., 2021b) and SOX4 (Du et al., 2026), alongside epigenetic remodeling by the histone demethylase JMJD3 (An et al., 2023), may cooperatively facilitate rapid and robust COX-2 mRNA induction. Furthermore, as a danger signal, 15d-PGJ2 may engage innate immune sensors such as the cGAS-STING pathway (Jiao et al., 2025) or the NLRP3 inflammasome (Li et al., 2025), both potent inducers of inflammatory gene expression and PGE2 production. Given that 15d-PGJ2 extensively modifies cytoskeletal proteins (Stamatakis et al., 2006), a connection to the Hippo pathway effector TEAD1 (Tran et al., 2025), which regulates mitochondrial function and prevents necroptosis and inflammation, also warrants consideration. Besides electrophilic stress, other receptor-independent mechanisms reported in other cell types—such as activation of membrane prostaglandin DP2/CRTH2 receptors, inactivation of MAPK phosphatases, or direct covalent modification of NF-κB signaling components—might also participate in 15d-PGJ2 signaling and warrant future exploration in mesangial cells. We fully acknowledge that these proposed alternative pathways remain speculative in the current study. Direct pharmacological or genetic targeting will be required in future investigations to establish their precise roles. Thus, 15d-PGJ2 acts as a dual-signaling molecule: a receptor agonist at low concentrations and a chemical stressor inducing pro-inflammatory cascades at higher concentrations, embodying the “dual-pathway” model that distinguishes systemic receptor-mediated actions from local tissue-level effects (Zhai et al., 2026). It is important to note that the increased PGE2 production observed in our study is attributed primarily to the upregulation of COX-2 expression, as evidenced by the corresponding increases in COX-2 mRNA and protein levels. However, we cannot entirely exclude the possibility that 15d-PGJ2 may also modulate COX-2 enzymatic activity or the expression/activity of terminal PGE2 synthases, such as microsomal prostaglandin E synthase-1 (mPGES-1) and mPGES-2, which have been shown to be expressed in kidney and to play important roles in PGE2 production (Wang et al., 2018; Yang et al., 2006). While our data demonstrate that 15d-PGJ2-induced COX-2 expression occurs independently of PPARγ, whether 15d-PGJ2 affects these downstream enzymes or directly modulates COX-2 activity remains to be determined. Future studies are needed to dissect these potential contributions to the overall increase in PGE2 production. Nevertheless, our conclusion that 15d-PGJ2 induces COX-2 expression through a PPARγ-independent mechanism remains robust, as it is based directly on the measurement of COX-2 mRNA and protein levels.

From a translational perspective, these findings provide important insights for drug discovery (Fang et al., 2021): Future design of 15d-PGJ2 analogs should aim to uncouple PPARγ-dependent anti-inflammatory genomic actions from electrophilic COX-2 induction (Thakur et al., 2023); In diseases where PGE2 is pathogenic, high-dose 15d-PGJ2 therapy might inadvertently counteract its intended therapeutic benefits (Chen et al., 2023); Systematic in vivo dose-response studies are required to define a safe therapeutic window where PPARγ is activated without triggering COX-2-mediated pro-inflammatory cascades. Furthermore, given the complex cellular architecture of the glomerulus, 15d-PGJ2-induced COX-2/PGE2 in mesangial cells likely exerts paracrine effects on neighboring podocytes and endothelial cells. A limitation of the present study is the exclusive use of monocultured mesangial cells. Future investigations utilizing glomerulus-on-a-chip, cell co-culture systems, or single-cell transcriptomics will be essential to elucidate how mesangial-derived prostaglandins shape the integrated glomerular microenvironment.

In conclusion, the present study demonstrates that the endogenous prostaglandin metabolite 15d-PGJ2 markedly induces COX-2 expression and enhances PGE2 production in primary cultured mouse mesangial cells via a mechanism independent of PPARγ. Using multiple independent approaches, including pharmacological inhibition, dominant-negative interference, siRNA-mediated knockdown, and genetic deletion, we provide compelling evidence that this induction occurs independently of PPARγ. These findings highlight a receptor-independent mechanism through which electrophilic lipid mediators regulate inflammatory gene expression in renal cells. Given the critical role of COX-2-derived prostaglandins in renal inflammation and disease progression, our results suggest that the biological effects of 15d-PGJ2 in the kidney may involve both PPARγ-dependent and independent pathways. This dual mode of action should be considered when evaluating the therapeutic potential of prostaglandin metabolites and PPARγ-targeting strategies in renal diseases.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This study was funded by the National Natural Science Foundation of China (Grant number 32171165).

Footnotes

Edited by: Krishna M. Boini, University of Houston, United States

Reviewed by: Wenlong Sun, Shandong University of Technology, China

Hao Du, Yale University, United States

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

The animal study was approved by Institutional Animal Care and Use Committee/Ethics Committee, Shanghai University of Medicine and Health Sciences (2025-NSFC-17-025). The study was conducted in accordance with the local legislation and institutional requirements.

Author contributions

BY: Conceptualization, Data curation, Formal Analysis, Investigation, Validation, Visualization, Writing – original draft, Writing – review and editing. YZ: Data curation, Investigation, Validation, Writing – review and editing. ZH: Investigation, Validation, Writing – review and editing. XF: Investigation, Validation, Writing – review and editing. XS: Investigation, Validation, Visualization, Writing – review and editing. XR: Investigation, Validation, Visualization, Writing – review and editing. GY: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review and editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  1. Agrawal S., He J. C., Tharaux P. L. (2021). Nuclear receptors in podocyte biology and glomerular disease. Nat. Rev. Nephrol. 17 (3), 185–204. 10.1038/s41581-020-00339-6 [DOI] [PubMed] [Google Scholar]
  2. An C., Jiao B., Du H., Tran M., Zhou D., Wang Y. (2022). Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II-induced hypertension. J. Cell Physiol. 237 (1), 983–991. 10.1002/jcp.30574 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. An C., Jiao B., Du H., Tran M., Song B., Wang P., et al. (2023). Jumonji domain-containing protein-3 (JMJD3) promotes myeloid fibroblast activation and macrophage polarization in kidney fibrosis. Br. J. Pharmacol. 180 (17), 2250–2265. 10.1111/bph.16096 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Asano T., Wakisaka M., Yoshinari M., Iino K., Sonoki K., Iwase M., et al. (2000). Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation. Biochim. Biophys. Acta 1497 (1), 148–154. 10.1016/s0167-4889(00)00054-9 [DOI] [PubMed] [Google Scholar]
  5. Ayoub S. S., Botting R. M., Joshi A. N., Seed M. P., Colville-Nash P. R. (2009). Activation of macrophage peroxisome proliferator-activated receptor-gamma by diclofenac results in the induction of cyclooxygenase-2 protein and the synthesis of anti-inflammatory cytokines. Mol. Cell Biochem. 327 (1-2), 101–110. 10.1007/s11010-009-0048-y [DOI] [PubMed] [Google Scholar]
  6. Bianchi A., Moulin D., Sebillaud S., Koufany M., Galteau M. M., Netter P., et al. (2005). Contrasting effects of peroxisome-proliferator-activated receptor (PPAR)gamma agonists on membrane-associated prostaglandin E2 synthase-1 in IL-1beta-stimulated rat chondrocytes: evidence for PPARgamma-independent inhibition by 15-deoxy-Delta12,14prostaglandin J2. Arthritis Res. Ther. 7 (6), R1325–R1337. 10.1186/ar1830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bianchi A., Moulin D., Hupont S., Koufany M., Netter P., Reboul P., et al. (2014). Oxidative stress-induced expression of HSP70 contributes to the inhibitory effect of 15d-PGJ2 on inducible prostaglandin pathway in chondrocytes. Free Radic. Biol. Med. 76, 114–126. 10.1016/j.freeradbiomed.2014.07.028 [DOI] [PubMed] [Google Scholar]
  8. Bie Q., Dong H., Jin C., Zhang H., Zhang B. (2018). 15d-PGJ2 is a new hope for controlling tumor growth. Am. J. Transl. Res. 10 (3), 648–658. [PMC free article] [PubMed] [Google Scholar]
  9. Chang Z., Xu X., Xu Y., Wei X., Yang G., Guo P., et al. (2025). Potential effects of functional foods and dietary supplements on metabolic-associated fatty liver disease and the underlying mechanisms: a narrative review with a focus on the modulation of the gut microbiota. J. Agric. Food Chem. 73 (46), 29247–29280. 10.1021/acs.jafc.5c05587 [DOI] [PubMed] [Google Scholar]
  10. Chawla A., Schwarz E. J., Dimaculangan D. D., Lazar M. A. (1994). Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135 (2), 798–800. 10.1210/endo.135.2.8033830 [DOI] [PubMed] [Google Scholar]
  11. Chen Q., Shinohara N., Abe T., Watanabe T., Nonomura K., Koyanagi T. (2004). Significance of COX-2 expression in human renal cell carcinoma cell lines. Int. J. Cancer 108 (6), 825–832. 10.1002/ijc.11646 [DOI] [PubMed] [Google Scholar]
  12. Chen H., Tan H., Wan J., Zeng Y., Wang J., Wang H., et al. (2023). PPAR-γ signaling in nonalcoholic fatty liver disease: pathogenesis and therapeutic targets. Pharmacol. Ther. 245, 108391. 10.1016/j.pharmthera.2023.108391 [DOI] [PubMed] [Google Scholar]
  13. Colca J. R., Tanis S. P., McDonald W. G., Kletzien R. F. (2014). Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases. Expert Opin. Investig. Drugs 23 (1), 1–7. 10.1517/13543784.2013.839659 [DOI] [PubMed] [Google Scholar]
  14. Du H., Jiao B., Xing J., Yang D., Tran M., Wang P., et al. (2026). Critical role of transcription factor SOX4 in tubular epithelial cell dedifferentiation and fibroblast activation during kidney fibrosis. Kidney Int. 109 (1), 101–118. 10.1016/j.kint.2025.08.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fahmi H., Pelletier J. P., Mineau F., Martel-Pelletier J. (2002). 15d-PGJ(2) is acting as a 'dual agent' on the regulation of COX-2 expression in human osteoarthritic chondrocytes. Osteoarthr. Cartil. 10 (11), 845–848. 10.1053/joca.2002.0835 [DOI] [PubMed] [Google Scholar]
  16. Fang S., Livergood M. C., Nakagawa P., Wu J., Sigmund C. D. (2021). Role of the peroxisome proliferator activated receptors in hypertension. Circ. Res. 128 (7), 1021–1039. 10.1161/circresaha.120.318062 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grosser T., Yu Y., Fitzgerald G. A. (2010). Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu. Rev. Med. 61, 17–33. 10.1146/annurev-med-011209-153129 [DOI] [PubMed] [Google Scholar]
  18. Guan Y. (2004). Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. J. Am. Soc. Nephrol. 15 (11), 2801–2815. 10.1097/01.Asn.0000139067.83419.46 [DOI] [PubMed] [Google Scholar]
  19. Guan Y., Breyer M. D. (2001). Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney Int. 60 (1), 14–30. 10.1046/j.1523-1755.2001.00766.x [DOI] [PubMed] [Google Scholar]
  20. Hernandez-Quiles M., Broekema M. F., Kalkhoven E. (2021). PPARgamma in metabolism, immunity, and cancer: unified and diverse mechanisms of action. Front. Endocrinol. (Lausanne) 12, 624112. 10.3389/fendo.2021.624112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hinz B., Brune K., Pahl A. (2003). 15-Deoxy-Delta(12,14)-prostaglandin J2 inhibits the expression of proinflammatory genes in human blood monocytes via a PPAR-gamma-independent mechanism. Biochem. Biophys. Res. Commun. 302 (2), 415–420. 10.1016/s0006-291x(03)00195-5 [DOI] [PubMed] [Google Scholar]
  22. Hirasawa Y., Muramatsu A., Suzuki Y., Nagamatsu T. (2006). Insufficient expression of cyclooxygenase-2 protein is associated with retarded degradation of aggregated protein in diabetic glomeruli. J. Pharmacol. Sci. 102 (2), 173–181. 10.1254/jphs.fpj06010x [DOI] [PubMed] [Google Scholar]
  23. Inoue H., Tanabe T., Umesono K. (2000). Feedback control of cyclooxygenase-2 expression through PPARgamma. J. Biol. Chem. 275 (36), 28028–28032. 10.1074/jbc.M001387200 [DOI] [PubMed] [Google Scholar]
  24. Jiao B., An C., Tran M., Du H., Wang P., Zhou D., et al. (2021a). Pharmacological inhibition of STAT6 ameliorates myeloid fibroblast activation and alternative macrophage polarization in renal fibrosis. Front. Immunol. 12, 735014. 10.3389/fimmu.2021.735014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jiao B., An C., Du H., Tran M., Wang P., Zhou D., et al. (2021b). STAT6 deficiency attenuates myeloid fibroblast activation and macrophage polarization in experimental folic acid nephropathy. Cells 10 (11), 3057. 10.3390/cells10113057 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jiao B., An C., Du H., Tran M., Yang D., Zhao Y., et al. (2025). Genetic deficiency or pharmacological inhibition of cGAS-STING signalling suppresses kidney inflammation and fibrosis. Br. J. Pharmacol. 182 (8), 1741–1762. 10.1111/bph.17412 [DOI] [PubMed] [Google Scholar]
  27. Kalajdzic T., Faour W. H., He Q. W., Fahmi H., Martel-Pelletier J., Pelletier J. P., et al. (2002). Nimesulide, a preferential cyclooxygenase 2 inhibitor, suppresses peroxisome proliferator-activated receptor induction of cyclooxygenase 2 gene expression in human synovial fibroblasts: evidence for receptor antagonism. Arthritis Rheum. 46 (2), 494–506. 10.1002/art.10055 [DOI] [PubMed] [Google Scholar]
  28. Kim J. W., Li M. H., Jang J. H., Na H. K., Song N. Y., Lee C., et al. (2008). 15-Deoxy-Delta(12,14)-prostaglandin J(2) rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: potential roles of akt and ERK1/2. Biochem. Pharmacol. 76 (11), 1577–1589. 10.1016/j.bcp.2008.08.007 [DOI] [PubMed] [Google Scholar]
  29. Kim E. H., Na H. K., Kim D. H., Park S. A., Kim H. N., Song N. Y., et al. (2008). 15-Deoxy-Delta12,14-prostaglandin J2 induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: a potential role of ROS. Carcinogenesis 29 (4), 688–695. 10.1093/carcin/bgm299 [DOI] [PubMed] [Google Scholar]
  30. Kitz K., Windischhofer W., Leis H. J., Huber E., Kollroser M., Malle E. (2011). 15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species. Free Radic. Biol. Med. 50 (7), 854–865. 10.1016/j.freeradbiomed.2010.12.039 [DOI] [PubMed] [Google Scholar]
  31. Kökény G., Calvier L., Legchenko E., Chouvarine P., Mózes M. M., Hansmann G. (2020). PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis. Curr. Opin. Nephrol. Hypertens. 29 (2), 171–179. 10.1097/mnh.0000000000000580 [DOI] [PubMed] [Google Scholar]
  32. Komers R., Epstein M. (2002). Cyclooxygenase-2 expression and function in renal pathophysiology. J. Hypertens. Suppl. 20 (6), S11–S15. [PubMed] [Google Scholar]
  33. Kömhoff M., Jeck N. D., Seyberth H. W., Gröne H. J., Nüsing R. M., Breyer M. D. (2000). Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int. 58 (6), 2420–2424. 10.1046/j.1523-1755.2000.00425.x [DOI] [PubMed] [Google Scholar]
  34. Konger R. L., Martel K. C., Jernigan D., Zhang Q., Travers J. B. (2010). The peroxisome proliferator-activated receptor gamma system regulates ultraviolet B-induced prostaglandin e(2) production in human epidermal keratinocytes. PPAR Res. 2010, 467053. 10.1155/2010/467053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lee J. H., Yu S. M., Yoon E. K., Lee W. K., Jung J. C., Kim S. J. (2007). 15-deoxy-Delta 12,14-ProstaglandinJ2 regulates dedifferentiation through peroxisome proliferator-activated receptor-gamma-dependent pathway but not COX-2 expression in articular chondrocytes. J. Korean Med. Sci. 22 (5), 891–897. 10.3346/jkms.2007.22.5.891 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Li W., Xie J., Yang L., Yang Y., Yang L., Li L. (2023). 15-deoxy-Δ(12,14)-prostaglandin J(2) relieved acute liver injury by inhibiting macrophage migration inhibitory factor expression via PPARγ in hepatocyte. Int. Immunopharmacol. 121, 110491. 10.1016/j.intimp.2023.110491 [DOI] [PubMed] [Google Scholar]
  37. Li H., Liu T., Shi X., Du H., Cai C., Yang D., et al. (2025). Mechanisms and therapeutic potential of pharmacological agents targeting inflammasomes. Biomed. Pharmacother. 189, 118164. 10.1016/j.biopha.2025.118164 [DOI] [PubMed] [Google Scholar]
  38. Lim H. J., Lee K. S., Lee S., Park J. H., Choi H. E., Go S. H., et al. (2007). 15d-PGJ2 stimulates HO-1 expression through p38 MAP kinase and Nrf-2 pathway in rat vascular smooth muscle cells. Toxicol. Appl. Pharmacol. 223 (1), 20–27. 10.1016/j.taap.2007.04.019 [DOI] [PubMed] [Google Scholar]
  39. Liu X., Yu H., Yang L., Li C., Li L. (2012). 15-Deoxy-Δ(12,14)-prostaglandin J(2) attenuates the biological activities of monocyte/macrophage cell lines. Eur. J. Cell Biol. 91 (8), 654–661. 10.1016/j.ejcb.2012.03.004 [DOI] [PubMed] [Google Scholar]
  40. Macia Guardado M., Lutz V., Hengstschläger M., Dolznig H. (2025). The role of prostaglandins as major inflammatory mediators in colorectal cancer. Int. J. Mol. Sci. 26 (24), 12191. 10.3390/ijms262412191 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nguyen G. (2006). Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor? Kidney Int. 70 (4), 618–620. 10.1038/sj.ki.5001723 [DOI] [PubMed] [Google Scholar]
  42. Park W. H. (2026). Eicosanoids and inflammation: a delicate balance of pro-inflammatory and pro-resolving mediators. Biochem. Pharmacol. 245, 117662. 10.1016/j.bcp.2025.117662 [DOI] [PubMed] [Google Scholar]
  43. Patel K. M., Wright K. L., Whittaker P., Chakravarty P., Watson M. L., Ward S. G. (2005). Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPAR(gamma) agonists: evidence for disparate functional effects which are independent of NF-(kappa)B and PPAR(gamma). Cell Signal 17 (9), 1098–1110. 10.1016/j.cellsig.2004.12.002 [DOI] [PubMed] [Google Scholar]
  44. Peh H. Y., Chen J. (2025). Pro-resolving lipid mediators and therapeutic innovations in resolution of inflammation. Pharmacol. Ther. 265, 108753. 10.1016/j.pharmthera.2024.108753 [DOI] [PubMed] [Google Scholar]
  45. Pereira M. P., Hurtado O., Cárdenas A., Boscá L., Castillo J., Dávalos A., et al. (2006). Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 cause potent neuroprotection after experimental stroke through noncompletely overlapping mechanisms. J. Cereb. Blood Flow. Metab. 26 (2), 218–229. 10.1038/sj.jcbfm.9600182 [DOI] [PubMed] [Google Scholar]
  46. Pontsler A. V., St Hilaire A., Marathe G. K., Zimmerman G. A., McIntyre T. M. (2002). Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein. J. Biol. Chem. 277 (15), 13029–13036. 10.1074/jbc.M109546200 [DOI] [PubMed] [Google Scholar]
  47. Reichman J., Cohen S., Goldfarb M., Shina A., Rosen S., Brezis M., et al. (2001). Renal effects of nabumetone, a COX-2 antagonist: impairment of function in isolated perfused rat kidneys contrasts with preserved renal function in vivo . Exp. Nephrol. 9 (6), 387–396. 10.1159/000052637 [DOI] [PubMed] [Google Scholar]
  48. Reyes-Martin P., Ramirez-Rubio S., Parra-Cid T., Bienes-Martínez R., Lucio-Cazana J. (2008). 15-Deoxy-delta12,14-prostaglandin-J(2) up-regulates cyclooxygenase-2 but inhibits prostaglandin-E(2) production through a thiol antioxidant-sensitive mechanism. Pharmacol. Res. 57 (5), 344–350. 10.1016/j.phrs.2008.03.007 [DOI] [PubMed] [Google Scholar]
  49. Rovin B. H., Wilmer W. A., Lu L., Doseff A. I., Dixon C., Kotur M., et al. (2002). 15-Deoxy-Delta12,14-prostaglandin J2 regulates mesangial cell proliferation and death. Kidney Int. 61 (4), 1293–1302. 10.1046/j.1523-1755.2002.00282.x [DOI] [PubMed] [Google Scholar]
  50. Sánchez-Gómez F. J., Cernuda-Morollón E., Stamatakis K., Pérez-Sala D. (2004). Protein thiol modification by 15-deoxy-Delta12,14-prostaglandin J2 addition in mesangial cells: role in the inhibition of pro-inflammatory genes. Mol. Pharmacol. 66 (5), 1349–1358. 10.1124/mol.104.002824 [DOI] [PubMed] [Google Scholar]
  51. Sawano H., Haneda M., Sugimoto T., Inoki K., Koya D., Kikkawa R. (2002). 15-Deoxy-Delta12,14-prostaglandin J2 inhibits IL-1beta-induced cyclooxygenase-2 expression in mesangial cells. Kidney Int. 61 (6), 1957–1967. 10.1046/j.1523-1755.2002.00351.x [DOI] [PubMed] [Google Scholar]
  52. Scoditti E., Massaro M., Carluccio M. A., Distante A., Storelli C., De Caterina R. (2010). PPARgamma agonists inhibit angiogenesis by suppressing PKCalpha- and CREB-mediated COX-2 expression in the human endothelium. Cardiovasc Res. 86 (2), 302–310. 10.1093/cvr/cvp400 [DOI] [PubMed] [Google Scholar]
  53. Stamatakis K., Sánchez-Gómez F. J., Pérez-Sala D. (2006). Identification of novel protein targets for modification by 15-deoxy-Delta12,14-prostaglandin J2 in mesangial cells reveals multiple interactions with the cytoskeleton. J. Am. Soc. Nephrol. 17 (1), 89–98. 10.1681/asn.2005030329 [DOI] [PubMed] [Google Scholar]
  54. Straus D. S., Glass C. K. (2007). Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28 (12), 551–558. 10.1016/j.it.2007.09.003 [DOI] [PubMed] [Google Scholar]
  55. Takeda K., Ichiki T., Tokunou T., Iino N., Takeshita A. (2001). 15-Deoxy-delta 12,14-prostaglandin J2 and thiazolidinediones activate the MEK/ERK pathway through phosphatidylinositol 3-kinase in vascular smooth muscle cells. J. Biol. Chem. 276 (52), 48950–48955. 10.1074/jbc.M108722200 [DOI] [PubMed] [Google Scholar]
  56. Thakur S., Dhapola R., Sarma P., Medhi B., Reddy D. H. (2023). Neuroinflammation in Alzheimer’s disease: current progress in molecular signaling and therapeutics. Inflammation 46 (1), 1–17. 10.1007/s10753-022-01721-1 [DOI] [PubMed] [Google Scholar]
  57. Tontonoz P., Hu E., Spiegelman B. M. (1994). Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79 (7), 1147–1156. 10.1016/0092-8674(94)90006-x [DOI] [PubMed] [Google Scholar]
  58. Tran M., Jiao B., Du H., Zhou D., Yechoor V., Wang Y. (2025). TEAD1 prevents necroptosis and inflammation in cisplatin-induced acute kidney injury through maintaining mitochondrial function. Int. J. Biol. Sci. 21 (2), 565–578. 10.7150/ijbs.104335 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tsubouchi Y., Kawahito Y., Kohno M., Inoue K., Hla T., Sano H. (2001). Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Delta(12,14)-prostaglandin J2. Biochem. Biophys. Res. Commun. 283 (4), 750–755. 10.1006/bbrc.2001.4847 [DOI] [PubMed] [Google Scholar]
  60. Wang J., Liu M., Zhang X., Yang G., Chen L. (2018). Physiological and pathophysiological implications of PGE(2) and the PGE(2) synthases in the kidney. Prostagl. Other Lipid Mediat. 134, 1–6. 10.1016/j.prostaglandins.2017.10.006 [DOI] [PubMed] [Google Scholar]
  61. Wang Y., Huang B., Wei X., Guan Y., Li L., Zheng Y., et al. (2026). Gut microbiota metabolic reprogramming drives the development of metabolic diseases in the host. Gut Microbes 18 (1), 2644681. 10.1080/19490976.2026.2644681 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wu J., Zhang Y., Wang N., Davis L., Yang G., Wang X., et al. (2004). Liver X receptor-alpha mediates cholesterol efflux in glomerular mesangial cells. Am. J. Physiol. Ren. Physiol. 287 (5), F886–F895. 10.1152/ajprenal.00123.2004 [DOI] [PubMed] [Google Scholar]
  63. Wu J., Chen L., Zhang D., Huo M., Zhang X., Pu D., et al. (2009). Peroxisome proliferator-activated receptors and renal diseases. Front. Biosci. (Landmark Ed) 14 (3), 995–1009. 10.2741/3291 [DOI] [PubMed] [Google Scholar]
  64. Yang G., Chen L., Zhang Y., Zhang X., Wu J., Li S., et al. (2006). Expression of mouse membrane-associated prostaglandin E2 synthase-2 (mPGES-2) along the urogenital tract. Biochim. Biophys. Acta 1761 (12), 1459–1468. 10.1016/j.bbalip.2006.06.018 [DOI] [PubMed] [Google Scholar]
  65. Yang Y., Gomez J. A., Herrera M., Perez-Marco R., Repenning P., Zhang Z., et al. (2015). Salt restriction leads to activation of adult renal mesenchymal stromal cell-like cells via prostaglandin E2 and E-prostanoid receptor 4. Hypertension 65 (5), 1047–1054. 10.1161/hypertensionaha.114.04611 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zhai S. Y., Li L. R., Jia J. H., Cao Y. X., Li M. Y., Zheng Y. F., et al. (2026). Food and medicine homology components ameliorate metabolic diseases via dual pathways: blood absorption and nonabsorptive pathways. Food Med. Homol. 3 (2), 9420080. 10.26599/FMH.2026.9420080 [DOI] [Google Scholar]
  67. Zhang Z. H., He J. Q., Zhao Y. Y., Chen H. C., Tan N. H. (2020). Asiatic acid prevents renal fibrosis in UUO rats via promoting the production of 15d-PGJ2, an endogenous ligand of PPAR-γ. Acta Pharmacol. Sin. 41 (3), 373–382. 10.1038/s41401-019-0319-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhou H., Xie X., Chen Y., Lin Y., Cai Z., Ding L., et al. (2020). Chaperone-mediated autophagy governs progression of papillary thyroid carcinoma via PPARγ-SDF1/CXCR4 signaling. J. Clin. Endocrinol. Metab. 105 (10). 10.1210/clinem/dgaa366 [DOI] [PubMed] [Google Scholar]
  69. Zhuang Y., Wang C., Wu C., Ding D., Zhao F., Hu C., et al. (2018). Mitochondrial oxidative stress activates COX-2/mPGES-1/PGE2 cascade induced by albumin in renal proximal tubular cells. Oncotarget 9 (10), 9235–9245. 10.18632/oncotarget.24187 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA

RESOURCES