More than one-third of patients with insulin-dependent diabetes mellitus (IDDM) will develop nephropathy and most of these will progress to renal failure. The cause of glomerulopathy in diabetes is unknown, although, in the early stages of diabetes glomerular filtration rate (GFR) is increased above normal and this hyperfiltration may cause glomerular damage. In diabetic rats, increased GFR occurs if hyperglycemia is moderate, and is due to glomerular vasodilation and increased glomerular plasma flows. If hyperglycemia is severe, opposite hemodynamic changes result in reduced GFR. Renal kallikrein, a protease which produces potent vasoactive kinins, is altered in patients with IDDM and in streptozotocin-diabetic rats. These kallikrein abnormalities parallel the abnormalities of renal plasma flow (RPF) and GFR described in severe and moderate hyperglycemia. Since the renal kallikrein-kinin system is thought to participate in regulating renal hemodynamics, it is plausible that renal kallikrein abnormalities in diabetes are responsible for altered RPF and GFR. As kinins stimulate the synthesis of prostaglandins and thromboxane in the kidney, and these autocoids are known to be produced in the glomerulus, altered glomerular function in diabetes might also be related to altered eicosanoid production. In this project, streptozotocin-diabetic rats will be studied to see if altered RPF or GFR are related to abnormalities in renal kallikrein, kinins, or eicosanoid production. Specifically, tissue levels and urinary excretion of kallikrein (active and prokallikrein) and urinary kinins will be measured, together with GFR and RPF in diabetic rats with various degrees of hyperglycemia. Glomerular synthesis and urinary excretion of vasoactive eicosanoids (PGE2, PGI2 and TXA2) will also be measured. In further testing the hypothesis, studies will examine the effects of kallikrein, kinin and eicosanoid inhibitors on RPF and GFR. The effects of dietary supplementation with eicosapentaenoic acid, a fatty acid known to alter tissue eicosanoid synthesis, on renal vasoactive factors and renal function will also be studied. To investigate the basis of observed renal kallikrein abnormalities, the effects of diabetes and insulin on prokallikrein synthesis and activation will be measured, using highly specific monoclonal antibodies. These studies may provide insight into renal dysfunction in diabetes and factors related to the pathophysiology of diabetic nephropathy, and provide a basis for subsequent clinical investigations.
