Effect of early diabetes mellitus on the glomerular renin-angiotensin system in the rat.

Abstract

One third of all diabetic patients develop kidney disease, or diabetic nephropathy. An important site of progressive injury in diabetic nephropathy is the glomerulus. Angiotensin II (Ang II) has been implicated as a key mediator in the progression of diabetic nephropathy. Ang II influences renal hemodynamics and modulates renal transport and growth. The intrarenal renin-angiotensin system (RAS) is responsible for local production of Ang II, independent of the systemic RAS. It is not known whether the glomerular RAS is involved in altered local Ang II production. Moreover, a number of studies have suggested downregulation of Ang II receptors in early diabetes, primarily attributed to the angiotensin type I (AT1) receptors. These studies determined the effect of early diabetes on the expression of components of the glomerular RAS, and on the status of a novel Ang II receptor, Ang II type 2 (AT 2) receptor. Three groups of rats were studied after two weeks: (1) control [C], (2) streptozotocin (STZ)-induced diabetes, with daily insulin to prevent ketosis but maintain hyperglycemia [D], and (3) STZ-induced diabetes, with normoglycemia maintained by insulin implants [D+I]. D rats had increased plasma glucose levels [C: 9.63 +/- 0.19 mM vs D: 37.79 +/- 1.63 mM (p < 0.001 vs C) vs D+I: 4.88 +/- 0.43 mM (p < 0.05 vs C); n = 12] and experienced renal hypertrophy, and a decrease in body weight compared to C and D+I rats. Plasma renin activity (PRA) was decreased in D but not significantly compared to C and D+I rats. Glomerular suspensions were isolated by sequential sieving after density gradient centrifugation. By competitive RT-PCR, D had no significant effect on glomerular mRNA expression of renin [C: 2,497.50 +/- 405 .03 vs D: 3,155.50 +/- 417.26 vs D+I: 2,490.00 +/- 645.80 fg mRNA/62.5 ng RNA; p = NS; n = 6], angiotensinogen (n = 4), or angiotensin converting enzyme (ACE: n = 5). By Western analysis, glomerular AT1 receptor protein expression was increased in D rats (341 +/- 127% of C; p < 0.05; n = 7), an effect partly reversed in D+I. By RT-PCR, AT2 receptor mRNA was increased in the cortex of D rats [C: 58,430 +/- 6,004 vs D: 83,675 +/- 3,575 vs D+I: 56,326 +/- 3,011 arbitrary units, (p < 0.005, D vs C and D+I); n = 6--7]. (Abstract shortened by UMI.)