TABLE 3.
Antifibrotic role of curcumin in urinary system fibrosis.
| Disease | Animal/cell model | Inducer | Dosage and duration | Described effects | Pathway | Reference |
|---|---|---|---|---|---|---|
| Renal fibrosis | In vitro: HKC | TGF-β1 (5 mg/mL) | Curcumin (3.125, 6.25, 12.5, 25, and 100 μmol/L for 72 h) | ↑: Retained epithelial morphology, a cobblestone growth pattern, E-cadherin, and cytokeratin ↓: Proliferation, vimentin and α-SMA, FSP 1-positive cells, p-AKT, mTOR, p70S6K, 4E-BP1, and eIF4E |
AKT/mTOR pathway | Zhu et al. (2017) |
| Renal fibrosis | In vivo: BALB/c mice (n = 48) | Clamping the renal pedicles with non-traumatic microaneurysm clamps | | ↑: APPL1 ↓: Serum creatinine (SCr), urea nitrogen, tubular epithelial cell injury, kidney injury, collagen deposition, fibrotic, collagen I, fibronectin (Fn), and ECM |
APPL1/AKT signaling pathway | Chen et al. (2018) |
| In vitro: EpiCM-a | | Curcumin (25 µM) | ↑: APPL1 ↓: p-AKT, collagen І, and Fn protein |
APPL1/AKT signaling pathway | ||
| Chronic kidney disease (CKD) | In vivo: female C57BL/6 mice (n = 72) | Cyclosporine A (15 mg/kg, s.c.) for 14 days | Curcumin (15 mg/kg/day, i.p.) for 14 days | ↓: PAI-1, α-SMA, and collagen I | - | Hu et al. (2016) |
| In vitro: HK-2 cells | Primary | | ↓: Proliferation, PAI-1, α-SMA, and collagen I | |||
| In vitro: HK-2-Si KL (klotho) cells | Primary Si KL | | ↑: PAI-1, α-SMA, and collagen I ↓: Klotho; Dnmt 1; methylation; and CpG249, 240, and 236 |
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| Acute kidney injury (AKI) and CKD | In vitro: HUVECs | TGF-β1 (5 mg/mL) | Curcumin solution (10 mg/mL) + ZnSO4 solution (1.61 mg/mL) | ↑: HIF-1α, VEGF, ROS, and cellular survival capacity and proliferation ↓: α-SMA, collagen I, Fn, and F-actin |
- | Zhang et al. (2022) |
| Peritoneal fibrosis | HMrSV5 | Dianeal (4.25%, 200 μL) | Curcumin (20, 40, and 80 μmol/L) | ↑: Cell viability and E-cadherin ↓: α-SMA, collagen I, Fn, TGF-β, p-TAK 1, p-JNK, and p-p38 |
EMT | Zhao et al. (2019a) |
| Tubulointerstitial fibrosis | In vitro: HK-2 cells | TGF-β1 (2.5 mg/mL) | Curcumin (10 μM) | ↑: PPARγ ↓: TβR-I, TβR-II, p-ERK, p-PPARγ, α-SMA, PAI-1, and E-cadherin -: p-Smad2 and p-Smad3 |
ERK | Li et al. (2013) |
| Renal fibrosis | In vivo: male SD rats (n = 30 + 40) | Cisplatin (4.5 mg/kg i.p. for 21 days) | Curcumin (300 mg/kg for 21 days) | ↑: Creatinine clearance, urea nitrogen, SCr, and urea levels in serum and urine, ↓: TGF-β1, α-SMA, HYP, Shh, Smo, Ptch, renal Gli1 and Gli2, fibrotic score, kidney injury score, tubular injury, and α-SMA (renal) |
Hedgehog signaling | Maghmomeh et al. (2019) |
| Chronic renal failure | Male SD rats (n = 70) | 5/6 Nephrectomy | Curcumin (75 mg/kg for 8 weeks) | ↑: Body weight ↓: Biochemical indexes (24-h urine volume, SBp, 24-h urine protein, blood urea nitrogen (BUN), SCr, and serum urea), glomerular diameter, HYP, p-mTOR, mTOR, p-P70S6K1, P70S6K1, P-4E-BP1, 4E-BP1, HIF-1α, and VEGF |
mTOR/HIF-1α/VEGF signaling pathway | Yangbiao He (2019) |
| Obstructive nephropathy | In vivo: male SD rats (n = 40) | Unilateral ureteral obstruction (UUO) | Curcumin (200 and 800 mg/kg for 14 days) | ↑: AP-1 ↓: Renal cortical NF-κB-DNA binding activity, ED-1-positive cell, type III collagen, MCP-1, TGF-β, PAI-1, ICAM-1, RANTES, collagen III |
NF-κB-dependent pathway | Kuwabara et al. (2006) |
| Nephrolithiasis | In vivo: male C57BL/6 mice (n = 32) | Glyoxylate (100 mg/kg for 1 week) | Curcumin (50 and 100 mg/kg for 14 days) | ↑: SOD, CAT, GPx, GR, GSH, HO-1, NQO1, UGT, NRF2, and p62↓: Calcium oxalate (CaOx), MDA, IL-6, MCP-1, OPN, CD44, α-SMA, collagen I, collagen fibril deposition, TUNEL-positive cells, Beclin-1, LC3 II, and LC3 II/I | NRF2 signaling pathway | Li et al. (2019) |
| Renal fibrosis | SD rats | 5/6 Nephrectomy | Curcumin (75 mg/kg for 8 weeks) | ↑: Plasma creatinine, right kidney weight, CCr, NRF2, HO-1, and GPX ↓: Creatinine clearance, oxidative stress, inflammation, renal fibrosis, left kidney weight, proteinuria, BUN, Keap-1, MDA, TNF-α, COX-2, NF-κB, and TGF-β -: Body weight, total cholesterol, triglyceride, and HDL cholesterol |
NRF2/Keap-1 | Soetikno et al. (2012) |
| Renal fibrosis | In vivo: 20 male Wistar rats | Cisplatin (5 mg/kg) i.p. | Curcumin (200 mg/kg) | ↑: CAT, NAG, GR, NRF2, claudin-2, occludin, E-cadherin, and β-catenin ↓: Plasma creatinine, BUN, MDA, NGAL, KIM-1, ATN, cleaved caspase 3, TGF-β1, collagen I, collagen IV, α-SMA, Hsp70/72, protein tyrosine nitration (3-NT), and PKC β2 |
Oxidative stress | Trujillo et al. (2016) |
| Renal interstitial fibrosis (RIF) | In vivo: male SD rats (n = 24) | UUO | Curcumin (200 mg/kg for 7 and 14 days) | ↑: Complex I, II, III, and IV; LC3B–LC3A ratio; and Beclin-1 ↓: Tubulointerstitial injury, RIF, collagen I, collagen III, NLRP3, caspase-1, IL-1β, MAVS, VDAC1, VDAC2, autophagosomes, PI3K, AKT, and mTOR |
PI3K/AKT/mTOR pathway | Lu et al. (2021a) |
| Chronic kidney disease (CKD) | In vivo: male SD rats | Monoclonal antibody OX-7 (2.2 mg/kg) | Curcumin (100 mg/kg) | ↑: HO-1 ↓: PAI-1, TGF-β, Fn, proteinuria, Fn production, and glomerular PAS-positive material |
TGF-β | Jens Gaedeke (2005) |
| AKI and CKD | In vitro: NRK-49F cells | TGF-β1 (5 mg/mL) | Curcumin solution (10 mg/mL) + ZnSO4 solution (1.61 mg/mL) | ↑: ROS, cellular survival capacity, and cellular proliferation ↓: α-SMA, collagen I, Fn (Fn), and F-actin |
TGF-β pathway | Zhang et al. (2022) |
| Renal fibrosis | In vivo: male C57 mice (n = 32) | UUO | Curcumin (50 and 100 mg/kg for 14 days) | ↑: PPARγ ↓: Collagen fibers, Fn, collagen I, α-SMA, PCNA, and p-Smad2/3 |
TGF-β1 signaling pathway | Zhou et al. (2014) |
| In vitro: NRK-49F cells | - | Curcumin (10, 20, and 30 μM) | ↑: ↓: Proliferation, α-SMA, PCNA, cyclin D1, and p-Smad2/3 |
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| In vitro: NRK-52E cells | Curcumin (10, 20, and 30 μM) | Proliferation (−) | ||||
| Renal fibrosis (unilateral ureteral obstruction) | In vivo: male SD rats (n = 30) | UUO | Curcumin (50 and 100 mg/kg for 8 weeks) | ↓: SCr, BUN levels, tubular injury, TGF-β1, P-Smad2/3, cleaved caspase-3, cleaved caspase-8, Dragon levels, and apoptosis | TGF-β1/Smad signaling pathway | Chen et al. (2021) |
| In vitro: HK-2 cells | TGF-β1 (5 mg/mL for 48 h) | Curcumin (10, 20, and 30 μM) | ↑: E-cadherin and vimentin ↓: Dragon, Fn, collagen I, collagen IV, and α-SMA |
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| Ischemia reperfusion injury (IRI) | In vitro: PC3 human prostate cells, LLC-PK1, and primary porcine kidney endothelial cells | Hypoxic atmosphere (95% N2, 5% O2, Bactal 2 gas Air Liquide) | Curcumin (65 mmol/L) | ↑: Viability ↓: Mitochondrial loss of function, endothelial activation, LDH, TLR4, P-selectin, ICAM1, TNF-α, and MCP 1 |
TLR | Thuillier et al. (2014) |
| RIF | In vivo: male C57 BL/6 mice (n = 18) | UUO | Curcumin (50 mg/kg/day for 14 days) | ↑: E-cadherin ↓: SCr, BUN, IL-1β, IL-6, TNF-α, TGF-β1, α-SMA, ECM collagen, vimentin, TLR4, and NF-κB P65 |
TLR4/NF-κB and PI3K/AKT signaling pathways | Wang et al. (2020) |
| In vitro: HK-2 cells | TGF-β1 (10 ng/mL for 48 h) | Curcumin (10 ng/mL for 48 h) | ↑: α-SMA and vimentin ↓: Viability, TLR4, NF-κB P65, IL-1β, IL-6, and TNF-α |
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| Diabetic nephropathy | In vivo: male Wistar rats | Streptozotocin (100 mg/kg body weight) | Curcumin (10 Mg/kg/day for 56 days) | ↑: Wnt 5α, β-catenin, and TOP–FOP ratio ↓: TGF-β1 and 8-OH-d |
Wnt/β-catenin/TGF-β1 | Ho et al. (2016) |
| Uric acid nephropathy | Male Wistar rats (n = 30) | Adenine (150 mg/kg) + potassium oxonate (250 mg/kg) oral gavage for 4 weeks | Curcumin (200 mg/kg for 8 weeks) | ↑: SCFAs, ZO-1, occluding, and claudin-1 ↓: Serum uric acid, SCr, BUN level, kidney index, and LPS |
Intestinal flora | Xu et al. (2021) |
| CKD | Male SD rats (n = 48) | Adenine (0.25% w/w in feed for 35 days) | Curcumin (37.5, 75, and 150 mg/kg for 35 days) | ↑: Plasma sclerostin concentrations, NRF2 (kidney), glutathione, diffuse acute tubular necrosis, interstitial fibrosis, apoptotic cells, dilatation of tubules, interstitial inflammatory cell infiltration, and tubular atrophy ↓: IL-1β, IL-6, TNF-α, and cystatin C -: BP |
- | Ali et al. (2017) |
| IRI | In vivo: large white male pigs | Clamping the right renal pedicle for 60 min with a vascular non-traumatic clamp | Curcumin (12 mg/mL) | ↑: IL-1Rn, complement C3, pro-fibrotic genes PAI-1, and vimentin ↓: Creatinine values (day 5, 7, 11, and 14), ED 1, CD 3, vimentin, and α-SMA |
- | Thuillier et al. (2014) |
| AKI and CKD | In vivo: male SD rats | 2/3 Nephrectomy | Curcumin solution (10 mg/mL) + ZnSO4 solution (1.61 mg/mL) | ↑: vWF ↓: α-SMA, SCr, and BUN -: ALT, AST, TP, and ALB |
- | Zhang et al. (2022) |
| CKD | In vitro: primary rat mesangial cells | - | Curcumin (10 μM) | ↑: HO-1 | - | Jens Gaedeke (2005) |