SRPK1 is a significant factor in driving the progression of diabetic kidney fibrosis

Abstract

Background

Diabetic nephropathy leads to renal fibrosis via excessive ECM accumulation. Current therapies lack specificity, highlighting the need to identify targets like SRPK1, whose role in diabetic kidney fibrosis remains unclear.

Methods

We investigated SRPK1’s function using a streptozotocin-induced diabetic nephropathy mice model and administered the selective SRPK1 inhibitor SRPIN340. Histological, biochemical, and molecular analyses were performed to assess ECM deposition, renal function, and fibrotic marker expression. Additionally, Western blotting and immunohistochemistry were utilized to explore the involvement of the NF-κB/NLRP3 signaling pathway.

Results

SRPK1 expression was significantly elevated in fibrotic kidneys, correlating with increased ECM components (collagen I/III, fibronectin) and reduced renal function. SRPIN340 treatment markedly alleviated ECM accumulation, improved glomerular filtration rate, and suppressed fibrotic markers (α-SMA, TGF-β). Mechanistically, SRPK1 activation promoted NF-κB/NLRP3 pathway activation, leading to inflammatory cytokine release (IL-1β, TNF-α) and fibrosis. Inhibition of SRPK1 via SRPIN340 abrogated these effects, suggesting a causal role for SRPK1 in fibrotic progression.

Conclusion

SRPK1 activates NF-κB/NLRP3 pathway, promoting ECM synthesis and inflammation in diabetic nephropathy; SRPIN340 reduces fibrosis, highlighting SRPK1 as a therapeutic target.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-025-01889-0.

Key messages

What is already known about this topic?

Diabetic nephropathy (DN) is one of the major complications of diabetes, with its core pathological feature being renal interstitial fibrosis. SRPK1 (serine/arginine protein kinase 1) has been confirmed to participate in the progression of diseases such as pulmonary fibrosis and hepatic fibrosis by regulating RNA splicing and signaling pathways. However, its specific role in renal fibrosis remains unclear.

What this study adds?

This study demonstrates that SRPIN340, as an SRPK1 inhibitor, effectively alleviates renal fibrosis in animal models, thereby providing experimental evidence for the clinical translation of SRPK1-targeted therapies.

How this study might affect research, practice, or policy?

This study advocates for prioritizing SRPK1-targeted inhibitors in the development of future therapeutic strategies for chronic kidney disease (CKD), while urging interdisciplinary collaboration that synergizes pharmacological research, bioinformatics analysis, and clinical resources to expedite the advancement of SRPK1-based therapeutics.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-025-01889-0.

Introduction

Diabetic nephropathy (DN) is a common complication of diabetes that affects the microvasculature in the kidneys and is the leading cause of end-stage renal disease [1, 2]. Inflammation and fibrosis of the renal interstitium are key pathological features of DN, closely linked to the prognosis of the disease [3]. Understanding the mechanism underlying renal interstitial fibrosis has long been a central focus in DN research. Previous studies have shown that progression of renal fibrosis involves significant proliferation and transformation of fibroblasts in the renal interstitium and surrounding blood vessels, leading to excessive accumulation of extracellular matrix, structural damage, and functional impairment of renal tissue [4–6]. However, our understanding of this precise underlying mechanism remains incomplete.

Our previous research has identified a peptide, AC-SDKP, which shows resistance to tissue fibrosis [7]. This peptide has demonstrated promising results in inhibiting excessive scar tissue formation and preventing the progression of fibrotic diseases such as pulmonary fibrosis and liver fibrosis. Subsequent investigations have revealed that the anti-fibrotic effect of AC-SDKP is attributed to its ability to inhibit the activity of SRPK1, a protein kinase [8]. Our preliminary investigation has confirmed the pivotal pro-fibrotic role of SRPK1 in both pulmonary and liver fibrosis. However, the precise role of SRPK1 in renal fibrosis remains incompletely understood, necessitating additional research to elucidate its potential implications in the pathogenesis of this condition.

Therefore, the primary focus of this study was to examine the involvement of SRPK1 in diabetic nephropathy fibrosis using animal models, while also investigating its potential mechanism for promoting renal fibrosis through in vitro cell models. We anticipate that these findings will offer valuable insights into the pathophysiology of diabetic nephropathy fibrosis.

Materials and methods

Animals

Male C57BL/6 mice (6–8 weeks, 150–250 g) were maintained in a sterile facility (18–26 °C, 40–70% humidity, < 85 dB) with sterilized diet/water and daily monitoring. All animal experimental protocols were approved by the Air Force Military Medical University Experimental Animals Ethics Committee (20241151. Xi’an, Shaanxi Province, China) to ensure the welfare and rights of experimental animals. Clinical trial number: not applicable.

IT2DM model and UUO model

IT2DM: IT2DM model: mice on regular diet vs. high-fat diet. STZ (50 mg/kg/day, pH4.5, 5 days IP) induced diabetes (FBG > 11.1 mmol/L). 30 models randomized into vehicle groups [10], IT2DM model groups [10] and SRPIN340 groups [10].

UUO: Anesthetize, position right-side down, shave, 0.5 cm dorsal incision. Expose peritoneum, access ureter, clamp mid-ureter, ligate/transect with silk suture. Post-op food/water ad libitum.30 models randomized into vehicle groups [10], UUO model groups [10] and SRPIN340 groups [10].

Primary cells were isolated and cultured

Mice euthanized by cervical dislocation were immersed in 75% alcohol for 5 min. Kidneys were aseptically extracted, and renal cortex dissected with a surgical blade. Collagenase and trypsin were used for digestion, followed by termination, filtration, centrifugation, and resuspension. Renal tubular epithelial cells were cultured in specialized medium.

Cell culture

The primary mouse cells were cultured in DMEM low glucose medium supplemented with 5% FBS and 1% penicillin-streptomycin, and maintained at 37 °C in a 5% CO₂ atmosphere. When the cells reached 90% confluence, they were dissociated using trypsin digestion solution for subculture.

High glucose (HG) culture medium stimulates cell activation at different time points

Cells were seeded at 1.5 × 10⁹/well in 6-well plates, serum-starved for 24 h at 60% confluence. HG medium (30mmol/L,0.5% FBS) was added at 0,6,12,24,36,48 h, while the control group received NG medium. Cultured at 37 °C in CO2 incubator. After treatment, cells were collected for protein extraction. Each group of experiments was independently repeated three times (n = 3).

Reagents and antibodies are used

BUN, Cr, SOD and MDA assay kits (Nanjing Jiancheng Bioengineering Institute, batch numbers A111-1-1, C013-2-1, C035-2-1); HE staining solution (Wuhan Saviour Biotech, CR2303063); RIPA lysis buffer, BCA protein concentration determination kit, protease inhibitor cocktail, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis gel preparation kit (Beijing BiyunTian, P0013K, P0012S, P1005, P0012A); FN1 antibody and immunohistochemistry assay kit (Wuhan Saviour Biotech, GB114491-100, G1215-200T). TGF-β1, α-SMA, Collagen -III, Collagen -I, SRPK1, Caspase-1, NLRP3, IL-1β, p-AMPK, GAPDH antibodies and horseradish peroxidase (HRP)-conjugated goat anti-rabbit immunoglobulin G (IgG) were purchased from Proteintech Group (China) with the following batch numbers: HZ-1011,14395-1-AP, HRP-22,734,CL594-67288,14073-1-AP,22915-1-AP,27458-1-AP, HZ-1164,83924-1-PBS, CL594-60004. Each group of experiments was independently repeated three times (n = 3).

A fully automated simultaneous detection method for FBG, TG, TC, and LDL-C in mouse serum

After an 8-hour fasting period, mice were anesthetized and 200 µL of venous blood was collected using EDTA anticoagulant. The serum was isolated by centrifugation at 4 °C (3000 rpm, 15 min). Biochemical parameters were measured using an automated biochemistry analyzer according to predefined protocols: Fasting blood glucose (FBG, glucose oxidase method, primary wavelength 505 nm); Triglycerides (TG, GPO-PAP method) and total cholesterol (TC, CHOD-PAP method); LDL-cholesterol (LDL-C, surfactant-based direct assay, primary wavelength 500 nm). High- and low-concentration quality control materials were analyzed prior to each batch. Acceptable intra-batch coefficients of variation (CV) were set at < 5% for TC/TG or < 8% for LDL-C, with recovery rates maintained at 95–105%. All procedures were completed within ≤ 3 h to minimize freeze-thaw cycles of samples.

Determination of Glycated hemoglobin (HbA1c)

After the last administration, all mice were fasted for 8 h with free access to water, anesthetized with ether, and approximately 500 µL of blood was collected via retro-orbital puncture into heparinized tubes. Glycated hemoglobin levels were determined using a commercially available mouse glycated hemoglobin ELISA kit according to the manufacturer’s instructions.

Western blot

Optimized sentence: The protein samples were mixed with a 4:1 ratio of 5× loading buffer for Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) and heated at 95 °C for 10 min. Subsequently, the proteins were separated by SDS-PAGE, transferred onto nitrocellulose membranes, and blocked with skim milk. Primary antibodies were incubated overnight. Following washing steps, the blots were incubated with secondary antibodies and subsequently exposed for analysis. All experiments were biologically replicated in three mice (n = 3).

Immunohistochemistry

Prepare paraffin sections and proceed with dewaxing, antigen retrieval, endogenous peroxidase blocking, serum blocking, primary antibody incubation, secondary antibody incubation, DAB staining, cell nuclei counterstaining, dehydration and slide sealing under a microscope. Utilize Image J software for integrated optical density (IOD) analysis. All experiments were biologically replicated in three mice (n = 10).

Immunofluorescence staining

Specimens were frozen, sectioned at 3 μm, washed with PBS 3 × 3 min, marked, incubated with rabbit anti-human fluorescein antibody at 37 °C in the dark for 30 min, rinsed, sealed with glycerol, and imaged using a fluorescence microscope. All experiments were biologically replicated in three mice (n = 10).

H&E

Mice euthanized with CO2 after 6 weeks. Kidneys isolated, washed, fixed in 4% PFA, decalcified with EDTA, embedded, sectioned at 4 μm, stained with H&E, dehydrated, sealed, and imaged using ImageJ software. All experiments were biologically replicated in three mice (n = 10).

Masson staining

Tissue slices were paraffin-embedded and dewaxed. Washed with distilled/deionized water, stained with Reagent A (Weigert A/B mix) for 10 min until nuclei turned blue. Dried at 55 °C for 5 min, then stained with Reagent Bfor 15 min. Removed excess B with Reagent C three times for 3 min each. Washed, treated with Reagent D for 5 min, followed by Reagent E for 10 s. Washed with water-soluble C, dehydrated with alcohol/xylene, and sealed with neutral resin. All experiments were biologically replicated in three mice (n = 10).

Sirius red staining

Tissue fixed with neutral formaldehyde, paraffin-sectioned and dewaxed. Stained with hematoxylin for 10 min, washed three times with distilled water, then stained with eosin Y for 30 min. Dehydrated in absolute alcohol, cleared with xylene, sealed with neutral gum. Collagen red, nuclei green, others yellow. All experiments were biologically replicated in three mice (n = 10).

Detection of renal function related indicators

Collect mouse blood and centrifuge it at a speed of 3000r/min for 20 min to separate the supernatant, which will be tested using a fully automated biochemical analyzer, an enzyme immunoassay analyzer, and corresponding reagent kits. All experiments were biologically replicated in three mice (n = 10).

Statistical analysis

Calculations and statistical analyses were executed with the R software package. Continuous variables were compared using either the two-tailed unpaired Student’s t-test or the two-tailed paired Student’s t-test with a signifcance threshold of P < 0.05,unless otherwise stated.

Results

SRPK1 is highly expressed in the fibrotic renal tissue

To validate the successful establishment of the diabetic renal fibrosis mouse model, we evaluated key serum biomarkers including fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). All measured parameters exhibited significant elevation in the model group compared to controls. Notably, the observed FBG and HbA1c levels met established diagnostic criteria for type 2 diabetic murine models, thereby confirming the validity of our experimental protocol (Table 1). A variety of methodologies were utilized to evaluate the expression of SRPK1 in fibrotic mouse kidney tissue. The results demonstrated that both approaches effectively induced fibrosis in the mouse kidney tissue, characterized primarily by a significant upregulation of the fibrotic marker protein α-SMA, (Fig. 1A-D). Additionally, it is worth noting that our main protein SRPK1 shows a significant increase in fibrotic tissues (Fig. E-F, G-H). Double immunofluorescence staining was performed to evaluate the co-localization of SRPK1 and α-SMA in renal fibrotic tissues. The results demonstrated that mice in the model group exhibited significantly enhanced co-localization of SRPK1 and α-SMA compared to their respective control groups (Fig. I-J). Preliminary evidence indicates a potential strong correlation between renal fibrosis and SRPK1.

Table 1.

Blood parameters of mice in different treatment groups

Group (n = 10)	FBG (mmol /L)	HbA1c (mmol /L)	TG (mmol /L)	TC (mmol /L)	LDL-C (mmol /L)
Control	5.43 ± 0.23	4.56 ± 0.87	1.17 ± 0.14	3.21 ± 0.57	0.13 ± 0.08
STZ + HFD	16.45 ± 4.08	9.31 ± 1.57	1.80 ± 0.73	5.43 ± 0.93	0.36 ± 0.02
P-value	< 0.001	0.015	0.034	0.028	0.031

Fig. 1.

SRPK1 exhibits elevated expression levels in fibrotic kidney tissue. Western blo and quantitative analysis was performed to evaluate the levels of α-SMA/SRPK1tin a murine model of diabetic kidney fibrosis (A, B) and UUO kidney fibrosis (C, D). IHC (E, F) and IF (G, H) was performed to evaluate the levels of SRPK1 in murine model of diabetic kidney fibrosis and UUO kidney fibrosis

Inhibition of SRPK1 results in reduced ECM synthesis and alleviated damage to kidney function

Renal fibrosis mouse model treated with PBS/SRPIN340 (6 weeks). HE staining revealed normal glomerular/tubular structure in controls vs. fibrotic kidneys with glomerular irregularity, tubular dilation, and inflammation; SRPIN340 treatment reduced damage and restored histological order (Fig. 2A-B). Masson/Sirius Red staining showed increased ECM deposition in renal fibrosis mice, which was reversed by SRPIN340 treatment (Fig. 2C-D). Kidney index, BUN, SCr, MDA, and SOD levels were measured via automated blood analysis. Renal fibrosis mice exhibited significantly elevated Cr, BUN, and MDA versus normal controls. However, after treatment with SRPIN340, it was observed that SRPIN340 significantly reduced the levels of Cr (Fig. 2E), BUN (Fig. 2F), and MDA (Fig. 2G) in the bloodstream of mice suffering from renal fibrosis. SOD plays a central protective role in renal fibrosis, as evidenced by its significant reduction in a murine model of diabetic renal fibrosis, which was partially alleviated following SRPIN340 administration (Fig. 2H). The above findings indicate that inhibiting SRPK1 can significantly improve renal injury in murine models of kidney fibrosis.

Fig. 2.

SRPIIN340 evaluation of renal tissue fibrosis and its impact on renal function after the administration of SRPIIN340. HE staining is used for evaluating the pathological structural changes of renal tissue, while Masson’s trichrome and Sirius red staining are employed to assess the deposition of ECM in diabetic kidney fibrosis (A) and UUO kidney fibrosis tissue (B). Assessment of chromium (C), BUN (D), MDA (E) levels, and kidney weight (F) as indicators for evaluating renal function in mice

Inhibition of SRPK1 results in reduced production of collagen and fibronectin in renal tissue

SRPK1 inhibition reduces collagen/fibronectin synthesis in renal ECM to combat fibrosis. Therefore, we aim to further investigate the potential of inhibiting SRPK1 in reducing the synthesis of collagen and fibronectin in renal tissue. The results showed that compared to normal mice, the up-regulation of Collagen I and FN-1 in renal tissues of mice with renal fibrosis was observed. However, treatment with SRPIN340 demonstrated an inhibitory effect on the expression of FN-1and Collagen I (Fig. 3A-F).

Fig. 3.

SRPIIN340 reduced production of collagen and fibronectin in renal tissue. IHC and quantitative analysis was performed to evaluate the levels of FN-1/Collagen III (A, B),FN-1/Collagen I (C, D) in murine model of diabetic kidney fibrosis. (E) IF was performed to evaluate the levels of α-SMA and Collagen I in murine model of diabetic kidney fibrosis. (F) IF was performed to evaluate the levels of α-SMA and Collagen I in murine model of UUO kidney fibrosis

Renal epithelial cells transform into α-SMA + myofibroblasts, integrating into Collagen I-rich ECM. The study findings indicate that compared to normal mice, the upregulation of collagen I and α-SMA was observed in renal tissue of mice with renal fibrosis, while administration of SRPIN340 showed an inhibitory effect on the expression of Collagen I and α-SMA (Fig. 3G-J). These results suggest that inhibition of SRPK1 may attenuate the expression of key extracellular matrix components such as collagen.

Inhibition of SRPK1 results in reduced expression of p-AMPK/p-p65/NLRP3 in renal tissue

Cell necrosis activates NF-kB p65, driving inflammation and ECM overproduction in renal fibrosis. NLRP3 inflammasome mediates pyroptosis, while AMPK phosphorylates SIRT1 to inhibit its activation. In our investigation, we observed a reduction in AMPK phosphorylation in the kidney tissue of mice with renal fibrosis, accompanied by activation of NF-kB p65. However, administration of SRPIN340 effectively suppressed the activation of NF-kB p65 (Fig. 4A-D). Furthermore, NLRP3, serving as a marker protein for cell pyroptosis, exhibited heightened expression in the kidney tissue of mice with renal fibrosis; yet treatment with SRPIN340 successfully attenuated the expression of NLRP3 (Fig. 4E-F).

Fig. 4.

SRPIIN340 decrease the expression of p-AMPK/p-p65/ NLRP3 in renal tissue. IHCand quantitative analysis (B) was performed to evaluate the levels of p-AMPK (A, B), p-p65 (C, D), NLRP3 (E, F) in murine model of diabetic kidney fibrosis and UUO kidney fibrosis

SRPK1 is involved in triggering pyroptosis in renal tubular cells through the AMPK signaling pathway

To further investigate the role of SRPK1 in cellular apoptosis in renal fibrosis, primary renal tubular cells were isolated and cultured. SRPIN340 reduced α-SMA expression in TGF-β1-stimulated renal tubular cells, mirroring SRPK1 inhibition (Fig. 5A, D). SRPIN340 increased p-AMPK and inhibited NF-kB p65 phosphorylation; TGF-β1 suppressed AMPK while promoting NF-kB p65 phosphorylation (Fig. 5B-C). Our research has shown that TGF-β1 increases the expression of NLRP3, Caspase-1, and IL-1β in renal tubular cells. However, treatment with SRPIN340 significantly reduces their expression. These findings indicate a potential role for TGF-β1 in promoting cell pyroptosis markers and emphasize the therapeutic potential of targeting this pathway (Fig. 5E-F). To investigate the involvement of SRPK1 in renal tubular cell apoptosis via the AMPK signaling pathway, we used SRPIN340 intervention and co-treated with the AMPK signaling pathway inhibitor Compound C. Our findings revealed that SRPIN340 + Compound C inhibited p-AMPK, increased p-NF-kB p65; NLRP3/IL-1β expression remained unchanged compared to SRPIN340 monotherapy (Fig. 5G-H).

Fig. 5.

SRPK1 is involved in triggering pyroptosis in renal tubular cells through the AMPK signaling pathway. Western blot and quantitative analysis was performed to evaluate the levels of α-SMA/SRPK1 (A, D), p-AMPK/p-p65 (B, C), Caspase-1/NLRP3/IL-1β/p-p65 (E, F), p-AMPK/p-p65/NLRP3/IL-1β, SRPIN340 intervention and co-treated with the AMPK signaling pathway inhibitor Compound C (G, H) in elevated glucose triggers the transformation of renal tubular epithelial cells

In vitro cell models with SRPK1 knockdown or overexpression were established. Western blot analysis showed that SRPK1 knockdown significantly decreased α-SMA protein expression, whereas SRPK1 overexpression markedly increased α-SMA levels. These findings are consistent withprior reports demonstrating SRPK1-dependent regulation of fibrotic responses (Fig. 6A-B). Further investigation revealed that SRPK1 depletion significantly increased phosphorylation of AMPK, concomitant with reduced phosphorylation of NF-κB p65. This inverse regulation suggests AMPK activation may suppress NF-κB signaling. Conversely, SRPK1 overexpression suppressed AMPK phosphorylation yet enhanced p65 phosphorylation ((Fig. 6C-D)). Importantly, these bidirectional effects on kinase cascades were mirrored in pyroptosis regulation: SRPK1 knockdown markedly downregulated key pyroptotic proteins, including NLRP3 (inflammasome component), cleaved caspase-1, and mature IL-1β; whereas SRPK1 overexpression elevated their levels (Fig. 6E-F), indicating SRPK1 orchestrates pyroptosis through the AMPK/NF-κB axis.

Fig. 6.

SRPK1 orchestrates pyroptosis through the AMPK/NF-κB axis. Western blot and quantitative analysis was performed to evaluate the levels of α-SMA/SRPK1 (A, D), p-AMPK/p-p65 (B, C), Caspase-1/NLRP3/IL-1β. (E, F), in elevated glucose triggers the cell models with SRPK1 knockdown or overexpression

Discussion

Interstitial fibrosis of the kidney is a prevalent complication of diabetes [9, 10]. Fibrosis ensues from an augmentation of fibrous connective tissue within an organ as a consequence of pathological alterations, leading to permanent scarring of the tissues, organ failure, and potentially death [11, 12]. Fibrosis is regarded as a significant contributor to morbidity and mortality in chronic inflammatory diseases [13]. Inflammation in the interstitium and vessels prompts fibroblast activation and ECM accumulation, thereby disrupting kidney structure and function [14]. Nevertheless, a comprehensive comprehension of this intricate process remains evasive.

Our previous research has shown that the novel anti-fibrotic peptide AC-SDKP targets SRPK1 [8], which is a splicing factor enzyme containing a phosphorylated serine/arginine-rich domain that primarily governs various stages of cell RNA maturation, chromatin recombination, cell cycle progression, and immune response [15, 16]. Dysregulation of SRPK1 has been implicated in the development of diseases such as cancer [17, 18]. However, the association between SRPK1 and tissue fibrosis remains unclear. In particular, its relationship with renal fibrosis has seldom been reported. Therefore, this study aims to further elucidate the role of SRPK1 in renal fibrosis based on our prior findings.

Recent studies have shown that pyroptosis is a newly discovered form of programmed cell death that relies on caspase-1 [19, 20]. When activated by specific stimuli, the inflammasome triggers pyroptosis, leading to cellular demise and the release of the pro-inflammatory cytokine IL-1β [21, 22]. Pyroptosis drives the necroptosis-inflammatory response-fibrosis axis, amplifying inflammation and exacerbating fibrosis [23, 24]. Our study investigated the potential pro-fibrotic role of SRPK1 in renal fibrosis by promoting cell pyroptosis. Our findings revealed a significant increase in the inflammatory mediator NLRP3 in the fibrosis model mice, and treatment with SRPIN340 effectively suppressed the expression of NLRP3, which is a crucial initiator of cell pyroptosis. These results indicate that SRPK1 modulates cell pyroptosis in renal tissue of fibrotic mice. Cell pyroptosis can lead to cellular membrane swelling and rupture, resulting in the release of inflammatory factors and activation of the NF-kB p65 signaling pathway, inducing inflammation.

SRPK1 activates NF-kB signaling to promote ECM secretion and fibrosis via pyroptosis. In vivo, SRPIN340 (SRPK1 inhibitor) restored AMPK phosphorylation while inhibiting NF-kB p65 activation. In vitro, SRPIN340 reduced TGF-β1-induced α-SMA expression, mimicking SRPK1 knockdown, and reversed AMPK inhibition/NF-kB activation. SRPIN340 increased p-AMPK and inhibited NF-kB p65 phosphorylation, reduced NLRP3/Caspase-1/IL-1β in TGF-β1-stimulated cells. Combined with Compound C (AMPK inhibitor), it potentiated apoptosis modulation. Our findings revealed that combined treatment with SRPIN340 and Compound C resulted in inhibition of AMPK phosphorylation, increased NF-kB p65 phosphorylation, while no significant shift was observed in NLRP3 and IL-1β expression compared to treatment with SRPIN340 alone. These results suggest a potential role for SRPK1 in promoting renal fibrosis by regulating renal tubular cell apoptosis via the AMPK signaling pathway.

Conclusion

SRPK1 acts as a pro-fibrotic mediator in DN-induced renal fibrosis, accelerating progression via extracellular matrix deposition. While its role as a therapeutic target emerges, mechanisms underlying SRPK1-AMPK crosstalk and apoptosis promotion remain undefined. Validation through multi-omics and longitudinal studies is warranted.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Shichao Han and Shuaijun Ma: Conceptualization, Methodology, Writing - Original Draft, Formal Analysis. Ruochen Qi, Kepu Liu and Guohui Wang: Formal Analysis, Data Interpretation, Writing - Review & Editing. Xutao Zhang and Weijun Qin: Supervision, Funding Acquisition, Writing - Review & Editing, Final Manuscript Approval. All authors contributed to manuscript revisions, approved the final version, and agreed to be accountable for all aspects of the work.

Funding

National Natural Science Foundation (82102322).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Institutional review board statement

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

AI tools were employed to enhance language quality and grammar during the preparation of this work. The manuscript was manually reviewed and edited by the authors to ensure accuracy and integrity. The authors retain full responsibility for the content and compliance with publication ethics.

Competing interests

The authors declare no competing interests.