Angiotensin II and its receptors in the diabetic kidney

Studies using either angiotensin-converting enzyme inhibitors or type 1 (AT (1)) angiotensin II (ANG II)-receptor blockers indicate that ANG II is a me diator of progressive injury in diabetic nephropathy, However, suppression of the systemic renin-angiotensin system (RAS) generally has been shown in diabetes mellitus, Evidence suggests that intrarenal RASs within glomeruli and proximal tubules may be activated with hyperglycemia, leading to stimul ation of local ANG II production, which may exert feedback inhibition of sy stemic renin release, Once formed, intrarenal ANG II exerts most of its wel l-described effects through binding to AT(1) receptors that are abundantly present in cells of the glomeruli, tubules, vasculature, and interstitium, Thus, AT(1)-receptor activation increases vascular resistance, reduces rena l blood flow, and stimulates production of extracellular matrix in the mesa ngium and tubulointerstitium, Recent studies suggest that the adult kidney also expresses type 2 (AT(2)) ANG II receptors in glomeruli, tubular segmen ts, and vasculature. AT(2)-receptor activation is associated with increased intrarenal nitric oxide production, stimulation of natriuresis, and inhibi tion of cell growth and matrix synthesis, effects that oppose those of kidn ey AT(1) receptors, A number of studies have shown a reduction in kidney AT (1)-receptor expression in diabetic nephropathy, suggesting that the balanc e between AT(1)- and AT(2)-receptor-mediated cell-signaling events may be a determinant of progression rate in diabetic nephropathy and that unopposed stimulation of AT(2) receptors by ANG II with use of AT(1)-receptor blocke rs may contribute to the beneficial propel-ties of these agents. Determinat ion of the expression pattern of AT(2) receptors in diabetes and further de finition of the role of AT(2) receptors in opposing the detrimental effects of AT(1) receptors may lead to more selective targeting of the RAS in diab etic nephropathy, (C) 2000 by the National Kidney Foundation, Inc.