Endothelial dilatory function predicts individual susceptibility to renal damage in the 5/6 nephrectomized rat

Abstract

In experimental animal models of renal disease the degree of renal damage varies between individuals. This could be caused by variation in the noxious event or by differences in individual susceptibility. Intact endothelial function is assumed to provide a defense mechanism against progressive renal damage. This study hypothesized that interindividual differences in renal endothelial function might be involved in individual susceptibility to renal damage, and it investigated whether endothelial function of small renal arteries before induction of 5/6 nephrectomy (5/6 Nx) in rats was related to development of renal damage after 5/6 Nx. Wistar rats underwent 5/6 Nx, and small renal arteries of the removed right kidney were investigated for endothelium-dependent relaxation to acetylcholine (ACh, 10(-8) to 10(-4) mol/L). The contribution of underlying endothelial dilative mediators, NO, prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF), was assessed using the inhibitors, L-NMMA, indomethacin, and charybdotoxin+apamin, respectively. After 5/6 Nx, proteinuria developed in each rat ranging from 22 to 278 (84 +/- 14) mg/24 h at week 5 (n = 23). Interestingly, a significant inverse correlation between individual ACh-relaxation (expressed as area under curve in arbitrary units) and proteinuria 5 wk after 5/6 Nx was found (r = -0.54; P = 0.008; n = 23). An inverse correlation was also found between individual NO contribution as well as PG contribution and proteinuria 5 wk after 5/6 Nx (r = -0.86, P = 0.001, n = 11; and r = -0.74, P = 0.01, n = 11, respectively). In addition, individual ACh-relaxation was positively correlated with GFR measured 6 wk after 5/6 Nx (r = 0.58; P = 0.016; n = 17). This study demonstrates for the first time that individual renal endothelial dilatory function of the healthy rat predicts susceptibility to renal damage after 5/6 Nx, which seems to depend on individual endothelial NO and PG activity.