Genetic predisposition to hypertension and microvascular injury in the remnant kidney model

Abstract

Genetic factors have been implicated in the development and progression of glomerulosclerosis and nephron loss in both experimental animals and in humans. The influence of a differing genetic predisposition to hypertension was examined in the remnant kidney (RK) model of progressive glomerulosclerosis. Dahl salt-sensitive (S) and salt-resistant (R) rats fed a normal salt diet underwent either sham surgery or approximately 5/6 renal ablation and were studied 2 to 3 weeks later. Renal ablation resulted in significantly more severe hypertension in RK-S rats (205 +/- 6.3 mm Hg, mean +/- SEM) compared with RK-R rats (153 +/- 3.5 mm Hg; p < 0.01). Renal autoregulatory ability, a protective mechanism against renal transmission of systemic hypertension, was normal in both S and R rats with intact renal mass. Renal ablation resulted in similar impairments of renal autoregulatory ability in both strains. However, striking differences in the severity of renal microvascular and glomerular injury were observed between the remnant kidneys of S and R rats, paralleling the differences in the severity of hypertension. The RK-S rats exhibited acute fibrinoid necrosis and thrombosis of glomerular capillaries, arterioles, and small arteries, whereas only mild segmental glomerulosclerosis lesions were observed in a small percentage of glomeruli in the RK-R rats. The intact kidneys of both strains were essentially free of glomerular or vascular lesions. These data suggest that a genetic predisposition to hypertension is a major determinant of the severity of hypertension that follows severe reduction of renal mass and the severity of the resulting hypertension, in turn, critically influences the severity of glomerular injury in the RK model.