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From the Division of Nephrology,*Baylor College of Medicine, Houston, Texas; the Division of Nephrology,University of Washington, Seattle, Washington; and the Division of Nephrology,Ewha Women’s University College of Medicine, Ewha Medical Research Center, Seoul, Korea
A loss of the microvascular endothelium occurs in the remnant kidney model of renal disease and may play an important role in progression (Kang et al, J Am Soc Nephrol, 12:1434, 2001). Given that nitric oxide (NO) is a potent endothelial cell survival factor, we hypothesized that stimulating (with L-arginine) or blocking (with nitro-L-arginine methyl ester, (L-NAME)) NO synthesis could modulate the integrity of the microvasculature and hence affect progression of renal disease. Rats underwent 5/6 nephrectomy (RK) and then were randomized at 4 weeks to receive vehicle, L-NAME, or L-arginine for 4 weeks. Systolic blood pressure and renal function was measured, and tissues were collected at 8 weeks for histological and molecular analyses. The effect of modulation of NO on vascular endothelial growth factor (VEGF) expression in rat aortic vascular smooth muscle cells (SMC) and mouse medullary thick ascending limb tubular epithelial cells (mTAL) was also studied. Inhibition of NO with L-NAME was associated with more rapid progression compared to RK alone, with worse blood pressure, proteinuria, renal function, glomerulosclerosis, and tubulointerstitial fibrosis. The injury was also associated with more glomerular and peritubular capillary endothelial cell loss in association with an impaired endothelial proliferative response. Interestingly, the preglomerular endothelium remained intact or was occasionally hyperplastic, and this was associated with a pronounced proliferation of the vascular SMCs with de novo expression of VEGF. Cell culture studies confirmed a divergent effect of NO inhibition on VEGF expression, with inhibition of VEGF synthesis in mTAL cells and stimulation of VEGF in vascular SMC. In contrast to the effects of NO inhibition, stimulation of NO with L-arginine had minimal effects in this rat model of progressive renal disease. These studies confirm that blockade of NO synthesis accelerates progression of renal disease in the remnant kidney model, and support the hypothesis that one of the pathogenic mechanisms may involve accelerated capillary loss and impaired angiogenesis of the renal microvasculature. Interestingly, inhibition of NO synthesis did not lead to a loss of the preglomerular endothelium, which may relate to the effect of NO blockade to stimulate VEGF synthesis in the adjacent vascular smooth muscle cell.
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