The intrarenal renin-angiotensin system and diabetic nephropathy.

The renin-angiotensin system (RAS) is a coordinated cascade of proteins and peptide hormones, the principal effector of which is angiotensin II (ANG II). Evidence now indicates that the kidney regulates its function via a self-contained RAS in a paracrine fashion. In diabetic nephropathy, the intrarenal generation of ANG II is increased, in spite of suppression of the systemic RAS. This increase can contribute to the progression of diabetic nephropathy via several hemodynamic, tubular and growth-promoting actions. ANG II induces insulin resistance. ANG II type-1 (AT(1)) and type-2 (AT(2)) receptors are downregulated in chronic diabetes, but decreased AT(2) receptor expression might contribute to early diabetic nephropathy by reducing AT(2) receptor-mediated beneficial actions that are counter-regulatory to those of the AT(1) receptor. AT(2) receptor stimulation might account for part of the renal protection seen with AT(1) receptor blockade. A rat model of accelerated diabetic nephropathy is the (mREN-2) 27 renin transgenic rat treated with streptozotocin in which both the intrarenal and extrarenal RAS is activated.