UP-REGULATION OF HSP47 IN THE MOUSE KIDNEYS WITH UNILATERAL URETERAL OBSTRUCTION

Background. Unilateral ureteral obstruction (UUO) is a well establishe d experimental model of renal injury leading to interstitial fibrosis. The molecular and cellular mechanism(s) of interstitial fibrosis in U UO are beginning to be elucidated. In the progression of interstitial fibrosis in UUO, up-regulation of collagen synthesis is commonly obser ved. HSP47 is a collagen-binding stress protein and is thought to be a collagen-specific molecular chaperone, which plays a pivotal role dur ing the biosynthesis and secretion of collagen molecules in the endopl asmic reticulum. The synthesis of HSP47 has been demonstrated to alway s parallel that of collagen in physiological and pathophysiological co nditions. It is well recognized that renin-angiotensin system (RAS) is enhanced in the setting of UUO and that enhanced RAS has been implica ted in the pathogenesis of interstitial fibrosis in the obstructed kid neys. Methods. To investigate the role of HSP47 in the progression of interstitial fibrosis in mouse UUO, the expression of HSP47 was examin ed by Northern blotting, immunohistochemistry and in situ hybridizatio n in the obstructed kidneys. To test the possible involvement of enhan ced RAS on the HSP47 expression, we examined the effects of lisinopril , an angiotensin converting enzyme inhibitor, on interstitial fibrosis , HSP47 and type I collagen mRNA expression. Results. By Northern blot analysis, HSP47 mRNA was significantly up-regulated at 12 hours (abou t twice that of sham operated kidneys) after the onset of ureteral obs truction, further increased and stayed at the increased level until se ven days (about 8 times that of sham operated kidneys). HSP47 mRNA and protein expression were observed in the periglomerular and peritubula r interstitial regions of the obstructed kidneys. Distribution of smoo th muscle a actin and type I collagen immunoreactivity were similar to the HSP47 distribution pattern, suggesting that HSP47 was up-regulate d in the myofibroblasts. Lisinopril ameliorated the expansion of corti cal interstitium in the obstructed kidneys at four and seven days afte r ureteral obstruction. HSP47 mRNA expression was suppressed at four a nd seven days, whereas type I collagen mRNA was suppressed only at sev en days after the onset of ureteral obstruction. Conclusions. These re sults demonstrate the early and persistent upregulation of HSP47 durin g the progression of interstitial fibrosis in mouse UUO kidneys, and f urther suggest the potential role of HSP47 in the pathogenesis of inte rstitial fibrosis in the obstructed kidneys. Partial suppression of HS P47 mRNA expression by lisinopril at day 4 and day 7 after ureteral ob struction suggests that there are other immediate trigger(s) that indu ce the HSP47 mRNA expression. Identification of the molecular mechanis m of HSP47 induction during UUO may give an insight into the novel asp ects of the molecular pathophysiology of interstitial fibrosis in obst ructive nephropathy.