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Am J Physiol Renal Physiol 284: F389-F398, 2003. First published October 22, 2002; doi:10.1152/ajprenal.00277.2002
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Vol. 284, Issue 2, F389-F398, February 2003

Reversibility of chronic cyclosporine nephropathy in rats after withdrawal of cyclosporine

Can Li1,2, Chul Woo Yang1, Wan Young Kim3, Ju Young Jung3, Jung Ho Cha3, Yong Soo Kim1, Jin Kim3, William M. Bennett4, and Byung Kee Bang1

Departments of 1 Internal Medicine and 3 Anatomy, The Catholic University of Korea, Seoul, Korea 137-701; 2 Nephrology and Dialysis Unit, Department of Internal Medicine, Affiliated Hospital, YanBian University Medical College, 133000 YanJi, JiLin, China; and 4 Cellular Transplantation Division, Legacy Good Samaritan Hospital, Portland, Oregon 97210

Renal interstitial inflammation is an important factor in the pathogenesis of chronic cyclosporin A (CsA) nephropathy. We studied the expression of the chemoattractant osteopontin (OPN) and the relationship between OPN expression and tubulointerstitial injury in a rat model of chronic CsA nephropathy. Chronic CsA nephropathy was induced in Sprague-Dawley rats by administering CsA (15 mg/kg sc) for 5 wk and then withdrawing it for 5 or 10 wk. Renal function, histopathology (arteriolopathy, ED-1-positive cells, and tubulointerstitial fibrosis), renin-angiotensin system (RAS) activity, and OPN expression were observed during the follow-up period. Renal function deteriorated in CsA-treated rats, with the development of typical histopathology and activation of RAS. After CsA withdrawal, these parameters were significantly reversed (all P < 0.05). The upregulation of OPN mRNA and protein expression seen in CsA-treated rat kidneys was decreased 5 wk after CsA withdrawal and was further decreased after 10 wk. Of note, OPN mRNA expression correlated with the number of infiltrating macrophage (r = 0.651, P < 0.01) and tubulointerstitial fibrosis (r = 0.729, P < 0.01). These findings suggest that OPN expression and macrophage infiltration decrease after long-term CsA withdrawal in rats with established chronic CsA nephropathy, and this is closely associated with recovery from renal injury.

cyclosporin withdrawal; osteopontin; macrophage; tubulointerstitial fibrosis; renin-angiotensin system


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