Mechanisms for Control of Renal Vascular Resistance in Type I Diabetes Mellitus

Abstract

Glomerular hyperfiltration and an increase in renal blood flow are hallmark characteristics of Type I_ Diabetes Mellitus in the early stages, and are major risk factors for the development of diabetic nephropathy. Previous studies from our laboratory have implicated an important role for the Nitric Oxide system. in mediating this response, because giving nitric oxide synthase inhibitors· 'prevented the increase in renal plasma flow and glomerular filtration rate during diabetes. However, a limitation of. these studies is that single point measurements were taken and may not reflect the time-dependent role of nitric oxide. Therefore, we have developed a more precise method to measure the role of nitric oxide in the chronic control of renal blood flow during diabetes. We measured renal blood flow continuously, 18 hr/day using a Transonic flow probe in control (C) and diabetic (D) rats. Renal blood flow averaged 8.0±0.1 and 7.8±0 ml/min in the .C and D groups, respectively, during the control period and induction of diabetes caused a marked and progressive increase in renal blood flow in the D rats, averaging 10±6% above control on day 1, and 22±3% and 34±1% above control by the end of diabetes weeks 1 and 2. During the control period, glomerular filtration rate averaged 2.1 ±0.1 and 1.7±0.1 ml/min in the C and D groups, respectively. Glomerular filtration rate did not change during the experiment in the C rats, but increased significantly in the D group, averaging 54±21 and 52±19% above control during diabetic weeks 1 and 2 and renal vascular resistance decreased significantly during the diabetic period. There were no significant changes in filtration fraction in either group. Importantly, chronic blockade of nitric oxide completely prevented the increase in renal blood flow and prevented the diabetes-induced hyperfiltration normally associated with diabetes. These data together suggest that nitric oxide is essential for the renal vasodilation caused by onset of type I diabetes and suggest that the renal vasodilation in diabetes occurs primarily at the afferent arteriole. Autoregulation of the afferent arteriole plays an important role in determining glomerular capillary hydrostatic pressure and glomerular filtration. In diabetes, renal autoregulation may be impaired, but the relative roles of myogenic and tubuloglomerular feedback mechanisms in controlling renal blood flow, and the time course of their involvement, is not known. In addition, there is very little known about autoregulatory mechanisms at the very onset of diabetes, before there has been time for renal structural changes to become manifest. Therefore, we designed experiments to establish the role of the myogenic response and tubuloglomerular feedback mechanism in renal blood flow. control at the onset of diabetes. Coupling continuous measurement of renal blood flow using Transonic flow probes and continuous measurement of arterial pressure, we were able to use transfer function analysis to determine the relationship between arterial pressure and renal blood flow .. This type of analysis examines the dynamic ability of the renal vasculature to attenuate, or autoregulate, the influence of the oscillatory power of blood pressure over the range of frequencies at which the myogenic response and tubuloglomerular feedback mechanism operate. In these studies we demonstrated that transfer function gain was negative, indicating effective· autoregulation, in the frequency range of the myogenic (0.1- 0.3 Hz) and tubuloglomerular feedback (0.03-0.06 Hz) mechanisms during control days. However, at the onset ·of diabetes gain increased to positive values and continued through the 2-week diabetic period. Chronic blockade of nitric oxide in diabetic rats normalized the increase in transfer function gain and possibly enhanced the autoregulatory response. Our model provides a novel method to measure the chronic effects of the nitric oxide on renal blood flow control during diabetes. By using this model we have demonstrated that nitric oxide is required for the immediate increase in renal blood flow in diabetes. Furthermore, these data suggest renal autoregulation is impaired at the onset of diabetes and may play a role in the increase in renal blood flow and glomerular filtration rate early in diabetes. In addition, these data together suggest that nitric oxide contributes to the impaired autoregulatory capacity of the renal vasculature.