Effect of Hydroxychloroquine on the Progression of Renal Injury in Chronic Uremic Rats

Yang, Ji Hye; Choi, Young Jin; Jin, Dong Chan; Yang, Chul Woo; Kim, Yong Soo; Bang, Byung Kee

Abstract

BACKGROUND: Hydroxychloroquine(HCQ) is known to inhibit proinflammatory cytokine production from stimulated mononuclear cells and to have anti-fibrotic effect. The aim of this study was to investigate if HCQ could ameliorate renal injury in chronic uremic rats.
METHODS
Using Sprague-Dawley rats, chronic uremia was induced by 5/6 nephrectomy. The rats were divided into 4 groups : normal control rats(NC), uremic control rats(UC) and uremic rats treated with HCQ 10 mg/kg/day(HCQ10) and 20 mg/kg/day (HCQ20). Blood pressure, renal functions, proteinuria and histological changes were followed up for 12 weeks. The glomerular monocyte/macrophage infiltration was evaluated by immunohistochemistry and mRNA expression of MCP-1 and TGF-beta1 was analyzed by RT-PCR.
RESULTS
Blood pressure was higher in UC than that in NC from 4 to 12 weeks, and it was lower in HCQ10(from 4 to 12 weeks) and HCQ20(at 4 week) than that in UC. BUN and serum creatinine levels were significantly higher in UC than those in NC from 4 to 12 weeks, and those were significantly decreased in HCQ10 and HCQ20 compared to UC. Creatinine clearance was significantly lower in UC than that in NC from 4 to 12 weeks, and it was increased in HCQ10 and HCQ20 compared to UC. 24 hour proteinurea was significantly increased in UC from 4 to 12 weeks compared to NC, and it was decreased in HCQ10 at 4 and 12 weeks compared to UC. Glomerulosclerosis score was minimal in NC, but was significantly increased in UC from 4 to 12 weeks. It was significantly decreased in HCQ10 and HCQ20 at 8 and 12 weeks compared to UC. Interstitial fibrosis score was also significantly increased in UC from 4 to 12 weeks compared to NC, and it was significantly decreased in HCQ10 and HCQ20 only at 4 weeks compared to UC. The number of glomerular infiltrated monocyte/macrophage in UC was higher than that in NC from 4 weeks, and was peak at 8 weeks. But it was comparable among NC, HCQ10 and HCQ20. MCP-1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ10 at 8 weeks compared to UC. TGF-beta1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ20 at 4 and 8 weeks compared to UC.
CONCLUSIONS
Our results suggest that HCQ inhibits MCP-1 and TGF-beta1 mRNA expression in renal cortical tissue and attenuates progression of glomerulosclerosis and interstitial fibrosis in chronic uremic rats, which lead to amelioration of renal function and decrease in proteinuria in chronic uremic rats.