Renal Hemodynamics In Experimental Diabetes Mellitus

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Several animal models of both Type 1 and Type 2 DM have been used to study the role of altered hemodynamics in the development of diabetic glomerulopathy [21-24]. As in diabetic patients, diabetic rats tend to exhibit reduced values for whole kidney GFR during periods of severe uncontrolled hyperglycemia; single nephron (SN) GFR and plasma flow rates are also normal or reduced in animals in such catabolic states [24]. In the more clinically applicable model of Type 1 diabetes with moderate hyperglycemia, whole kidney GFR and SNGFR increase by about 40% as compared to normal rats [24-26]. Reductions in intrarenal vascular resistances result in elevation of the glomerular capillary plasma flow rate, QA. Despite normal blood pressure levels, transmission of systemic pressures to the glomerular capillaries is facilitated by proportionally greater reductions in afferent compared to efferent arteriolar resistances. Consequently, the glomerular capillary hydraulic pressure (PGC) rises. Thus, the observed single nephron hyperfiltration results from both glomerular capillary hyperperfusion and hypertension [24-26]. In longterm studies, diabetic rats develop morphologic changes reminiscent of those in the diabetic human, including glomerular basement membrane thickening, renal and glomerular hypertrophy, mesangial matrix thickening and hyaline deposition, and ultimately glomerular sclerosis [25-30].

Evidence that these glomerular hemodynamic maladaptations contribute to the development and progression of diabetic glomerulopathy has been shown by studies of maneuvers which aggravate or ameliorate glomerular hyperperfusion and hyperfiltration, without affecting metabolic control. Uninephrectomy, which increases SNGFR, QA and PGC in normal rats, accelerates the development of albuminuria and glomerular sclerosis in diabetic rats [31]. Intensification of glomerular lesions is observed in the unclipped kidney of diabetic rats with two-kidney Goldblatt hypertension, while the clipped kidney is substantially protected from glomerular injury [32]. Diabetic renal injury is similarly amplified by augmentation of dietary protein content, which increases glomerular perfusion and filtration [25].

By contrast, dietary protein restriction, which reduces SNGFR, QA and PGC in other models, has clarified the role of hemodynamic factors in diabetic glomerulopathy. In long-term diabetes, low protein diets limited SNGFR by reducing the elevated PGC and QA, and virtually prevented albuminuria and glomerular injury. In contrast, diabetic rats fed a high protein diet exhibited glomerular capillary hyperfiltration, hyperperfusion and hypertension, and marked increases in albuminuria and glomerular morphologic injury [25]. As there were no differences in metabolic control between the various groups, this study provided clear evidence that amelioration of the maladaptive glomerular hemodynamic pattern could prevent diabetic renal disease could dramatically lower the risk of diabetic glomerulopathy.

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