Renal ischemia-reperfusion induces a dysbalance of angiopoietins, accompanied by proliferation of pericytes and fibrosis

Abstract

Endothelial cells (ECs) are highly susceptible to hypoxia and easily affected upon ischemia-reperfusion (I/R) during renal transplantation. Pericytes and angiopoeitins play important role in modulating EC function. In the present study, we investigate the effect of renal I/R on the dynamics of angiopoietin expression and its association with pericytes and fibrosis development. Male Lewis rats were subjected to unilateral renal ischemia for 45 min followed by removal of the contralateral kidney. Rats were killed at different time points after reperfusion. Endothelial integrity (RECA-1), pericytes [platelet-derived growth factor receptor-β (PDGFR-β)], angiopoietin-2 (Ang-2)/angiopoietin-1 (Ang-1) expression, and interstitial collagen deposition (Sirius red and α-smooth muscle actin) were assessed using immunohistochemistry and RT-PCR. Our study shows an increase in protein expression of Ang-2 starting at 5 h and remaining elevated up to 72 h, with a consequently higher Ang-2/Ang-1 ratio after renal I/R ( P < 0.05 at 48 h). This was accompanied by an increase in protein expression of the pericytic marker PDGFR-β and a loss of ECs (both at 72 h after I/R, P < 0.05). Nine weeks after I/R, when renal function was restored, we observed normalization of the Ang-2/Ang-1 ratio and PDGFR-β expression and increase in cortical ECs, which was accompanied by fibrosis. Renal I/R induces a dysbalance of Ang-2/Ang-1 accompanied by proliferation of pericytes, EC loss, and development of fibrosis. The Ang-2/Ang-1 balance was reversed to baseline at 9 wk after renal I/R, which coincided with restoration of cortical ECs and pericytes. Our findings suggest that angiopoietins and pericytes play an important role in renal microvascular remodeling and development of fibrosis.