Regulation of Renal Function in Diabetes Mellitus

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

1. Substantial efforts have been expended to elucidate the mechanisms underlying the development and prevention of diabetic nephropathy. There is considerable evidence from experimental animal studies that maintenance of a normal hydrostatic pressure within the glomerular microcirculation is an important prerequisite for maintaining structural integrity. Protecting the glomerular capillaries from the blood pressure variations in the systemic circulation is the function of renal autoregulatory mechanisms that change renal vascular resistance in parallel to blood pressure. Using a rat model of type 2 diabetic rats, the OLETF rats (Otsuka Long-Evans Tokushima Fatty strain of rats, developed in Japan) we investigated in both pre-diabetic (12 weeks old) and diabetic rats (24 weeks old) whether renal hemodynamic abnormalities, specifically abnormalities in renal autoregulation, exist and whether they precede the onset of diabetes. Using a manual clamp on the abdominal aorta, we measured renal blood flow as well as superficial and deep nephron blood flow in response to comparable reductions of renal perfusion pressure. Whereas no significant differences in the response of superficial blood flow were found between OLETF rats and control rats, the perfusion pressure reduction decreased deep nephron blood flow significantly more in OLETF than control rats. Micropuncture studies showed that compared to control rats tubuloglomerular feedback (TGF) responses were reduced in prediabetic (7.3 v.s 25.7% reduction of Psf) as well as in diabetic OLETF rats (4.4 v.s. 18.8%). Renal corticotomy was performed to measure glomerular capillary pressure directly. Glomerular capillary pressure in OLETF rats was significantly higher in deep than superficial nephrons (782 v.s. 574 mm Hg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region suggesting that hemodynamic dysregulation early in life is a risk factor for developing renal disease.