Treatment with a PPAR-γ Agonist Protects Against Hyperuricemic Nephropathy in a Rat Model

Overview

Journal Drug Des Devel Ther

Specialty Pharmacology

Date 2020 Jul 2

PMID 32606592

Citations 12

Authors

Xin Wang

Jin Deng

Chongxiang Xiong

Haishan Chen

Qin Zhou

Yue Xia

Xiaofei Shao

Hequn Zou

Affiliations

Soon will be listed here.

Abstract

Purpose: Hyperuricemia is an independent risk factor for renal damage and can promote the progression of chronic kidney disease (CKD). In the present study, we employ a rat model to investigate the effects of rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor-gamma agonist, on the development of hyperuricemic nephropathy (HN), and we elucidate the mechanisms involved.

Methods: An HN rat model was established by oral administration of a mixture of adenine and potassium oxonate daily for 3 weeks. Twenty-four rats were divided into 4 groups: sham treatment, sham treatment plus RGTZ, HN, and HN treated with RGTZ.

Results: Administration of RGTZ effectively preserved renal function, decreased urine microalbumin, and inhibited interstitial fibrosis and macrophage infiltration in a rat HN model. RGTZ treatment also inhibited TGF-β and NF-κB pathway activation, decreased expression of fibronectin, collagen I, α-SMA, vimentin, MCP-1, RANTES, TNF-α, and IL-1β, and increased E-cadherin expression in the kidneys of HN rats. Furthermore, RGTZ treatment preserved expression of OAT1 and OAT3 in the kidney of HN rats.

Conclusion: RGTZ attenuates the progression of HN through inhibiting TGF-β signaling, suppressing epithelial-to-mesenchymal transition, reducing inﬂammation, and lowering serum uric acid levels by preserving expression of urate transporters.

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References

Spiga R, Marini M, Mancuso E, Di Fatta C, Fuoco A, Perticone F . Uric Acid Is Associated With Inflammatory Biomarkers and Induces Inflammation Via Activating the NF-κB Signaling Pathway in HepG2 Cells. Arterioscler Thromb Vasc Biol. 2017; 37(6):1241-1249. DOI: 10.1161/ATVBAHA.117.309128. View

Zhou Y, Fang L, Jiang L, Wen P, Cao H, He W . Uric acid induces renal inflammation via activating tubular NF-κB signaling pathway. PLoS One. 2012; 7(6):e39738. PMC: 3382585. DOI: 10.1371/journal.pone.0039738. View

Otani N, Ouchi M, Hayashi K, Jutabha P, Anzai N . Roles of organic anion transporters (OATs) in renal proximal tubules and their localization. Anat Sci Int. 2016; 92(2):200-206. DOI: 10.1007/s12565-016-0369-3. View

Liu Y . Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011; 7(12):684-96. PMC: 4520424. DOI: 10.1038/nrneph.2011.149. View

Huang H, Liu Y, Daniluk J, Gaiser S, Chu J, Wang H . Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology. 2012; 144(1):202-10. PMC: 3769090. DOI: 10.1053/j.gastro.2012.09.059. View

Bao Y, Zhao T, Wang X, Qiu Y, Su M, Jia W . Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. J Proteome Res. 2009; 8(4):1623-30. DOI: 10.1021/pr800643w. View

Gutting T, Weber C, Weidner P, Herweck F, Henn S, Friedrich T . PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant mice. Oncoimmunology. 2018; 7(5):e1423168. PMC: 5927516. DOI: 10.1080/2162402X.2017.1423168. View

Black L, Lever J, Agarwal A . Renal Inflammation and Fibrosis: A Double-edged Sword. J Histochem Cytochem. 2019; 67(9):663-681. PMC: 6713973. DOI: 10.1369/0022155419852932. View

Kadam L, Gomez-Lopez N, Mial T, Kohan-Ghadr H, Drewlo S . Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth. Reprod Sci. 2017; 24(12):1590-1599. PMC: 6728562. DOI: 10.1177/1933719117697128. View

10.

Wang P, Luo M, Song E, Zhou Z, Ma T, Wang J . Long noncoding RNA inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway. Sci Transl Med. 2018; 10(462). DOI: 10.1126/scitranslmed.aat2039. View

11.

Stone R, Pastar I, Ojeh N, Chen V, Liu S, Garzon K . Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016; 365(3):495-506. PMC: 5011038. DOI: 10.1007/s00441-016-2464-0. View

12.

Jalal D, Chonchol M, Chen W, Targher G . Uric acid as a target of therapy in CKD. Am J Kidney Dis. 2012; 61(1):134-46. PMC: 3525781. DOI: 10.1053/j.ajkd.2012.07.021. View

13.

Liu N, Xu L, Shi Y, Fang L, Gu H, Wang H . Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats. Oncotarget. 2017; 8(20):33807-33826. PMC: 5464913. DOI: 10.18632/oncotarget.16995. View

14.

Ryu E, Kim M, Shin H, Jang Y, Choi H, Jo I . Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol. 2013; 304(5):F471-80. DOI: 10.1152/ajprenal.00560.2012. View

15.

Jiang L, Chen X, Long Y, Lei F, Zhou Z, Qin Y . The potential signaling pathway between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha in renal interstitial fibrosis disease. J Recept Signal Transduct Res. 2014; 35(4):258-68. DOI: 10.3109/10799893.2014.975249. View

16.

Wu W, Bush K, Nigam S . Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes. Sci Rep. 2017; 7(1):4939. PMC: 5504054. DOI: 10.1038/s41598-017-04949-2. View

17.

Zhu T, Chen Z, Chen G, Wang D, Tang S, Deng H . Curcumin Attenuates Asthmatic Airway Inflammation and Mucus Hypersecretion Involving a PPAR-Dependent NF-B Signaling Pathway In Vivo and In Vitro. Mediators Inflamm. 2019; 2019:4927430. PMC: 6470457. DOI: 10.1155/2019/4927430. View

18.

Huijuan W, Xiaoxu C, Rui S, Xinghui L, Beibei T, Jianchun M . Qi-Zhu-Xie-Zhuo-Fang reduces serum uric acid levels and ameliorates renal fibrosis in hyperuricemic nephropathy rats. Biomed Pharmacother. 2017; 91:358-365. DOI: 10.1016/j.biopha.2017.04.031. View

19.

Lee Y, Han H . Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells. Am J Physiol Renal Physiol. 2009; 298(5):F1263-75. DOI: 10.1152/ajprenal.00475.2009. View

20.

Chou H, Wen L, Chang C, Lin C, Jin L, Juan S . From the Cover: l-Carnitine via PPARγ- and Sirt1-Dependent Mechanisms Attenuates Epithelial-Mesenchymal Transition and Renal Fibrosis Caused by Perfluorooctanesulfonate. Toxicol Sci. 2017; 160(2):217-229. DOI: 10.1093/toxsci/kfx183. View