Role of angiotensin II in diabetic nephropathy

Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting en zyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II a ction may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells t o induce sclerosis independent of its hemodynamic actions. To study nonhemo dynamic effects of Ang II on matrix metabolism, many investigators have use d cell culture systems. Glucose and Ang II have been shown to produce simil ar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plas min) activity. Glucose and Ang II also can inhibit proximal tubule proteina ses. Glucose increases expression of the angiotensinogen gene in proximal t ubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin syste m. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangi al cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced incremen t in TGF-beta secretion. Taken together, these findings support the hypothe sis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TG F-beta 1 secretion, leading to increased synthesis and decreased degradatio n of matrix proteins, thus producing matrix accumulation. This may be an im portant mechanism linking hyperglycemia and Ang II in the pathogenesis of d iabetic nephropathy.