Several systemic or intrarenal networks of
cytokines and
growth factors can be modulated by the diabetic state. We summarize the status of the renin-angiotensin system in
diabetes mellitus and review the evidence of its involvement in the pathogenesis of
diabetic nephropathy. Particular emphasis is placed on the nonhemodynamic properties of this vasoactive agent as both a renal
growth factor and a profibrogenic
peptide. Antagonizing the effects of
angiotensin II with converting
enzyme inhibitors is an established protective strategy in the management of
diabetic nephropathy even in the absence of systemic
hypertension. This and other indirect evidence from experimental animal studies suggest that the intrarenal concentration of
angiotensin II may be increased as a result of increased synthesis and despite enhanced breakdown, that this
peptide participates in the progression of
diabetic nephropathy. However, down-regulation of
angiotensin type 1 (AT1)-receptors is one of the abnormalities of both tubules and glomeruli in diabetic renal disease. A heightened bioactivation of the intrarenal
angiotensin II system is therefore likely but not certain. Studies in cultured proximal tubular and glomerular mesangial cells have disclosed striking similarities between the effects of high
glucose-containing medium and of treatment with
angiotensin II on the growth properties and the induction of
cytokines in these cells. There may also exist additive effects of
angiotensin II and high
glucose on signal-transduction pathways, such as activation of
protein kinase C, although the contractile response to
angiotensin II may be blunted by high
glucose in mesangial cells. An important downstream mediator of the effects of both
angiotensin II and high
glucose is the activation of
transforming growth factor-beta that can mediate at least some of the hypertrophic and profibrotic effects of either
angiotensin II or high
glucose in the diabetic kidney.