Induction of p27KIP1 after unilateral ureteral obstruction is independent of angiotensin II

Background. Unilateral ureteral obstruction (UUO) is characterized by proliferation of tubular and interstitial cells, and infiltration of the renal parenchyma with macrophages/monocytes. These alterations lead ultimately to tubulointerstitial fibrosis and tubular atrophy. Some of these changes are caused by an activated renin-angiotensin system (RAS). We have previously demonstrated that angiotensin It induces the expression of the cell cycle inhibitor p27(KIP1) in cultured tubular cells. The current study tested the hypothesis that interference with the RAS may modulate renal expression of p27(KIP1) after UUO. Methods. The ureter of the left kidney of Sprague-Dawley rats was ligated. Sham-operated animals served as controls. Rats were randomized in four groups and received one of the following: no therapy. enalapril, losartan, or triple therapy (hydralazine, reserpine, hydrochlorothiazide). Kidneys were removed and cortical protein lysates were prepared for the detection of p27(KIP1) by Western blotting. Immunohistochemistry was performed for p27(KIP1). PCNA. ED-1. and a-smooth muscle actin. Apoptosis was quantified by TUNEL-staining. Results. p27(KIP1) expression as detected by Western blotting reached a maximum 10 days after UUO. Tubular and interstitial cells contributed to this increase in p27(KIP1) expression whereas the number of glomerular p27(KIP1) positive cell did not change. p27(KIP1)-positive cells were macrophages/monocytes (positive ED-1 staining) or had the characteristics of myofibroblasts (positive alpha -smooth muscle actin staining). Tubular and interstitial proliferation [proliferating cell nuclear antigen (PCNA)-positive-staining] and apoptosis [terminal deoxy transferase uridine triphosphate nick end labeling (TUNEL) staining] also was increased after UUO. However, individual cells stained either positive for p27(KIP1) or PCNA, but not both. Although enalapril and losartan reduced the number of macrophages/monocytes and attenuated the degree of tubular and interstitial apoptosis, these drugs did not influence P27(KIP1) expression. There was no change in the number of p27(KIP1)-positive cells in the contralateral kidney undergoing hypertrophy. Conclusion. Induction of p27(KIP1) in this model represents an endogenous response to likely limit proliferation that is independant of angiotensin II. Since there was no close correlation between apoptosis and p27(KIP1) expression, it may be that the overall number of p27(KIP1) expressing cells sets a general restriction point for apoptosis rather than defines an individual level of cell fate.