Oridonin Attenuates Diabetes‑induced Renal Fibrosis via the
                    Inhibition of TXNIP/NLRP3 and NF‑κB Pathways by Activating PPARγ in
                    Rats

Gengzhen Huang; Yaodan Zhang; Yingying Zhang; Xiaotao Zhou; Yuan Xu; Huiting Wei; Xian Chen; Yuerong Ma

doi:10.1055/a-2322-7438

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2024; 132(10): 536-544
DOI: 10.1055/a-2322-7438

Article

Oridonin Attenuates Diabetes‑induced Renal Fibrosis via the Inhibition of TXNIP/NLRP3 and NF‑κB Pathways by Activating PPARγ in Rats

Autoren

Gengzhen Huang‡

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China

²Chengdu Second people's Hospital, Chengdu, China
Yaodan Zhang‡

³Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
Yingying Zhang‡

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China
Xiaotao Zhou

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China
Yuan Xu

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China
Huiting Wei

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China
Xian Chen

³Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
Yuerong Ma

¹Chengdu University of Traditional Chinese Medicine, Chengdu, China

Abstract

Introduction Oridonin possesses remarkable anti-inflammatory, immunoregulatory properties. However, the renoprotective effects of oridonin and the underlying molecular mechanisms in diabetic nephropathy (DN). We hypothesized that oridonin could ameliorate diabetes‑induced renal fibrosis.

Methods Streptozocin (STZ)-induced diabetic rats were provided with a high-fat diet to establish a type 2 diabetes mellitus (T2DM) animal model, and then treated with Oridonin (10, 20 mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. High glucose-induced human renal proximal tubule epithelial cells (HK-2) were also treated with oridonin. The expression of inflammatory factors and fibrotic markers were analyzed.

Results Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the oridonin 10 mg/kg/day and 20 mg/kg/day groups compared to the T2DM group. The expression of thioredoxin-interacting proteins/ nod-like receptor protein-3 (TXNIP/NLRP3) and nuclear factor (NF)‑κB pathway decreased, while that of peroxisome proliferator-activated receptor-gamma (PPARγ) increased in the oridonin treatment group compared to the non-treated group. In vitro, PPARγ intervention could significantly regulate the effect of oridonin on the high glucose-induced inflammatory changes in HK-2 cells.

Conclusion Oridonin reduces renal fibrosis and preserves kidney function via the inhibition of TXNIP/NLRP3 and NF‑κB pathways by activating PPARγ in rat T2DM model, which indicates potential effect of oridonin in the treatment of DN.

Keywords

oridonin - diabetes - renal fibrosis - NLRP3 - PPARγ

Volltext

Referenzen

References
1 Cooper M, Warren AM. A promising outlook for diabetic kidney disease. Nat Rev Nephrol 2019; 15: 68-70
2 Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017; 12: 2032-2045
3 Thomas MC, Brownlee M, Susztak K. et al. Diabetic kidney disease. Nat Rev Dis Primers 2015; 1: 15018
4 Bonner R, Albajrami O, Hudspeth J. et al. Diabetic kidney disease. Prim Care 2020; 47: 645-659
5 Reidy K, Kang HM, Hostetter T. et al. Molecular mechanisms of diabetic kidney disease. J Clin Invest 2014; 124: 2333-2340
6 Singh R, Barden A, Mori T. et al. Advanced glycation end-products: A review. Diabetologia 2001; 44: 129-146
7 Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 2016; 12: 13-26
8 Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol 2020; 16: 206-222
9 He W, Rebello O, Savino R. et al. TLR4 triggered complex inflammation in human pancreatic islets. Biochim Biophys Acta Mol Basis Dis 2019; 1865: 86-97
10 Alibashe-Ahmed M, Brioudes E, Reith W. et al. Toll-like receptor 4 inhibition prevents autoimmune diabetes in NOD mice. Sci Rep 2019; 9: 19350
11 Han W, Ma Q, Liu Y. et al. Huangkui capsule alleviates renal tubular epithelial-mesenchymal transition in diabetic nephropathy via inhibiting NLRP3 inflammasome activation and TLR4/NF-κB signaling. Phytomedicine 2019; 57: 203-214
12 Gu Y, Wu X, Zhang J. et al. The evolving landscape of N(6)-methyladenosine modification in the tumor microenvironment. Mol Ther 2021; 29: 1703-1715
13 Fusco R, Siracusa R, Genovese T. et al. Focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci 2020; 21: 4223.
14 Jiang H, Gong T, Zhou R. The strategies of targeting the NLRP3 inflammasome to treat inflammatory diseases. Adv Immunol 2020; 145: 55-93
15 Qiu YY, Tang LQ. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol Res 2016; 114: 251-264
16 Alhawiti NM, Al Mahri S, Aziz MA. et al. TXNIP in metabolic regulation: Physiological role and therapeutic outlook. Curr Drug Targets 2017; 18: 1095-1103
17 Monagle P, Cuello CA, Augustine C. et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: Treatment of pediatric venous thromboembolism. Blood Adv 2018; 2: 3292-3316
18 Thielen L, Shalev A. Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP. Curr Opin Endocrinol Diabetes Obes 2018; 25: 75-80
19 Tang Y, Wei K, Liu L. et al. Activation of PPARγ protects obese mice from acute lung injury by inhibiting endoplasmic reticulum stress and promoting mitochondrial biogenesis. PPAR Res 2022; 2022: 7888937
20 Zhang Y, Huang X, Zhou J. et al. PPARγ provides anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway. Biochem Biophys Res Commun 2018; 504: 834-842
21 Tao L, Wu L, Zhang W. et al. Peroxisome proliferator-activated receptor γ inhibits hepatic stellate cell activation regulated by miR-942 in chronic hepatitis B liver fibrosis. Life Sci 2020; 253: 117572
22 Cataldi S, Costa V, Ciccodicola A. et al. PPARγ and diabetes: Beyond the genome and towards personalized medicine. Curr Diab Rep 2021; 21: 18
23 Abd El Motteleb DM, Abd El Aleem DI. Renoprotective effect of Hypericum perforatum against diabetic nephropathy in rats: Insights in the underlying mechanisms. Clin Exp Pharmacol Physiol 2017; 44: 509-521
24 Reddy AT, Lakshmi SP, Banno A. et al. Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress. Free Radic Biol Med 2018; 126: 350-357
25 He H, Jiang H, Chen Y. et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun 2018; 9: 2550
26 Zhou L, Sun L, Wu H. et al. Oridonin ameliorates lupus-like symptoms of MRL(lpr/lpr) mice by inhibition of B-cell activating factor (BAFF). Eur J Pharmacol 2013; 715: 230-237
27 Li J, Bao L, Zha D. et al. Oridonin protects against the inflammatory response in diabetic nephropathy by inhibiting the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways. Int Immunopharmacol 2018; 55: 9-19
28 Stavniichuk A, Hye Khan MA, Yeboah MM. et al. Dual soluble epoxide hydrolase inhibitor/PPAR-γ agonist attenuates renal fibrosis. Prostaglandins Other Lipid Mediat 2020; 150: 106472
29 Cao L, Qin P, Zhang J. et al. LncRNA PVT1 suppresses the progression of renal fibrosis via inactivation of TGF-β signaling pathway. Drug Des Devel Ther 2020; 14: 3547-3557
30 Yu Y, Jiang H, Niu Y. et al. Long noncoding RNA-GAS5 retards renal fibrosis through repressing miR-21 activity. Exp Mol Pathol 2020; 116: 104518
31 Huang JH, Lan CC, Hsu YT. et al. Oridonin attenuates lipopolysaccharide-induced ROS accumulation and inflammation in HK-2 cells. Evid Based Complement Alternat Med 2020; 2020: 9724520
32 Huang W, Huang M, Ouyang H. et al. Oridonin inhibits vascular inflammation by blocking NF-κB and MAPK activation. Eur J Pharmacol 2018; 826: 133-139
33 Jia T, Cai M, Ma X. et al. Oridonin inhibits IL-1β-induced inflammation in human osteoarthritis chondrocytes by activating PPAR-γ. Int Immunopharmacol 2019; 69: 382-388
34 Yang H, Lv H, Li H. et al. Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways. Cell Commun Signal 2019; 17: 62
35 Bohanon FJ, Wang X, Ding C. et al. Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis. J Surg Res 2014; 190: 55-63
36 Liu D, Qin H, Yang B. et al. Oridonin ameliorates carbon tetrachloride-induced liver fibrosis in mice through inhibition of the NLRP3 inflammasome. Drug Dev Res 2020; 81: 526-533
37 Wu M, Han W, Song S. et al. NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice. Mol Cell Endocrinol 2018; 478: 115-125
38 Yue Y, Meng K, Pu Y. et al. Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract 2017; 133: 124-130
39 Ziller N, Kotolloshi R, Esmaeili M. et al. Sex differences in diabetes- and TGF-β1-induced renal damage. Cells. 2020 9. 2236
40 Tuleta I, Frangogiannis NG. Diabetic fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867: 166044
41 Zhang N, Guan C, Liu Z. et al. Calycosin attenuates renal ischemia/reperfusion injury by suppressing NF-κB mediated inflammation via PPARγ/EGR1 pathway. Front Pharmacol 2022; 13: 970616
42 Salama SA, Elshafey MM. Cross-talk between PPARγ, NF-κB, and p38 MAPK signaling mediates the ameliorating effects of bergenin against the iron overload-induced hepatotoxicity. Chem Biol Interact 2022; 368: 110207
43 Hu X, Hong B, Sun M. Peitu shengjin recipe attenuates airway inflammation via the TLR4/NF-kB signaling pathway on chronic obstructive pulmonary disease. Evid Based Complement Alternat Med 2022; 2022: 2090478