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C/EBP-β Modulates Transcription of Tubulointerstitial Nephritis Antigen in Obstructive Uropathy

Ping Xie^*, Lin Sun^*,, Baibasawata Nayak^*, Yoshisuke Haruna^*, Fu-you Liu, Naoki Kashihara and Yashpal S. Kanwar^*

^* Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois; Department of Nephrology, 2nd Xiangya Hospital Central S. University, Changsha, China; and Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

Correspondence: Dr. Yashpal S. Kanwar, Department of Pathology, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611. Phone: 312-503-0004; Fax: 312-503-0627; E-mail: y-kanwar{at}northwestern.edu

Received for publication September 23, 2008. Accepted for publication November 30, 2008.

Tubulointerstitial injury leading to fibrosis is a common pathway of many renal diseases. During this type of injury, modeled by unilateral ureteral obstruction (UUO), cells undergo epithelial-to-mesenchymal transition (EMT), a process that is mediated by various cytokines that modulate the biology of extracellular matrix proteins. Here, we studied the tubulointerstitial nephritis antigen (TINag), a tubular basement membrane protein, in the UUO model of tubulointerstitial injury. We observed upregulation of type IV collagen but downregulation of both laminin and TINag in obstructed kidneys. TINag downregulation was a result of oxidative stress; in the proximal tubular epithelial cell line HK-2, TINag expression and its promoter activity decreased after treatment with H₂O₂. We identified multiple CCAAT/enhancer binding protein β (C/EBP-β) motifs in the TINag promoter and observed that oxidant stress perturbed interactions between TINag DNA and C/EBP-β protein. Oxidant stress reduced nuclear translocation of C/EBP-β in HK-2 cells, which was restored by antioxidants. In addition, overexpression of C/EBP-β restored the H₂O₂-induced reduction of TINag promoter activity and expression. Furthermore, in vivo, renal obstruction reduced nuclear expression of C/EBP-β. Cells grown on a TINag substratum maintained their normal epithelial phenotype and cytoskeletal organization, similar to those grown on type IV collagen, and demonstrated reduced synthesis of fibronectin. Taken together, these findings suggest that altered interactions between C/EBP-β and TINag play a critical role in the pathophysiology of renal injury after obstruction.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673