title: Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease.
abstract: Recent experimental and clinical studies suggest a causal role of uric acid in the development of chronic kidney disease. Most studies have focused on uric acid-induced endothelial dysfunction, oxidative stress, and inflammation in the kidney. The direct effects of uric acid on tubular cells have not been studied in detail, and whether uric acid can mediate phenotypic transition of renal tubular cells such as epithelial-to-mesenchymal transition (EMT) is not known. We therefore investigated whether uric acid could alter E-cadherin expression and EMT in the kidney of hyperuricemic rats and in cultured renal tubular cells (NRK cells). Experimental hyperuricemia was associated with evidence of EMT before the development of significant tubulointerstitial fibrosis at 4 wk, as shown by decreased E-cadherin expression and an increased α-smooth muscle actin (α-SMA). Allopurinol significantly inhibited uric acid-induced changes in E-cadherin and α-SMA with an amelioration of renal fibrosis at 6 wk. In cultured NRK cells, uric acid induced EMT, which was blocked by the organic anion transport inhibitor probenecid. Uric acid increased expression of transcriptional factors associated with decreased synthesis of E-cadherin (Snail and Slug). Uric acid also increased the degradation of E-cadherin via ubiquitination, which is of importance since downregulation of E-cadherin is considered to be a triggering mechanism for EMT. In conclusion, uric acid induces EMT of renal tubular cells decreasing E-cadherin synthesis via an activation of Snail and Slug as well as increasing the degradation of E-cadherin.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, 911 Mok-dong Yangcheon-Ku, Seoul 158-710, Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Ryu
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Shin
authors.forename: Yang-Hee
authors.initials: YH
authors.lastname: Jang
authors.forename: Hack Sun
authors.initials: HS
authors.lastname: Choi
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D033461:Hyperuricemia / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology*; D014527:Uric Acid / Q000097:blood*; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D003404:Creatinine; D014527:Uric Acid; D014746:Vimentin; C498862:Acta2 protein, rat