Renin-Angiotensin System

It has been suggested that these intraglomerular hemodynamic abnormalities are due to altered vasoactive hormone action. This would imply an imbal- ance in the actions of vasoconstrictors and vasodilators in the diabetic kidney and has resulted in a large body of research focusing on a range of vasoactive hormones and their receptors in the genesis not only of the initial hemodynamic abnormalities but also on the subsequent glomerular ultrastructural injury. The system most extensively investigated is the renin-angiotensin system (RAS) which involves a series of enzymatic reactions leading to the production of the effector peptide, angiotensin II (AII). This hormone has a diverse range of actions including vasoconstriction, stimulation of sodium reabsorption and of particular interest trophic effects on a range of cells including mesangial cells. These actions are considered relevant to the postulated mode of action of agents which interrupt the RAS such as ACE inhibitors and AII receptor antagonists. All components of the RAS are present in the kidney, consistent It has been suggested that these intraglomerular hemodynamic abnormalities are due to altered vasoactive hormone action. This would imply an imbal- ance in the actions of vasoconstrictors and vasodilators in the diabetic kidney and has resulted in a large body of research focusing on a range of vasoactive hormones and their receptors in the genesis not only of the initial hemodynamic abnormalities but also on the subsequent glomerular ultrastructural injury. The system most extensively investigated is the renin-angiotensin system (RAS) which involves a series of enzymatic reactions leading to the production of the effector peptide, angiotensin II (AII). This hormone has a diverse range of actions including vasoconstriction, stimulation of sodium reabsorption and of particular interest trophic effects on a range of cells including mesangial cells. These actions are considered relevant to the postulated mode of action of agents which interrupt the RAS such as ACE inhibitors and AII receptor antagonists. All components of the RAS are present in the kidney, consistent

Evidence of a role for the RAS in the genesis of diabetic complications has been provided by a range of studies using different experimental techniques.

Although it was initially considered that diabetes was associated with a sup- pressed RAS, primarily based on studies assessing the systemic RAS, Anderson et al. have identified sites of local activation of the RAS within the kidney including the glomerulus and other renal vessels. Indeed, in a series of experi- ments using molecular biological and immunohistochemical techniques in an animal model of renal disease, the subtotal nephrectomy model, which has many functional and structural similarities to diabetic nephropathy, our group has shown that with renal injury there is de novo expression of various components of the RAS including renin and AII within the kidney. This local activation of the RAS particularly in the proximal tubule may be particularly important as a potential mechanism for the development of tubulointerstitial fibrosis in advanced diabetic nephropathy. Similar changes have recently been observed by our group in an animal model of advanced DN.

To further explore the role of the RAS in the evolution of DN, diabetes has been induced in transgenic Ren 2 rats, a rat strain generated by insertion of the mouse renin Ren 2 gene into their genome. This hypertensive strain has elevated prorenin levels and the induction of diabetes leads to the rapid development of glomerulosclerosis, tubulointerstitial injury and renal impair- ment which can be attenuated by ACE inhibition. This provides further evidence for a role for the RAS, particularly at the local level, in mediating renal injury in diabetes.

The importance of the RAS is of particular relevance to the management of DN. Agents which interrupt the RAS such as ACE inhibitors and AII receptor antagonists have been shown to attenuate the development of experimental DN. These agents normalize intraglomerular pressure, suppress renal cytokine production and prevent extracellular matrix accumulation. These beneficial effects observed in rodents have also been reproduced in man. In various phases of human DN in the presence or absence of systemic hyperten- sion, ACE inhibitors have been shown to reduce urinary albumin excretion and retard the decline in GFR. Whether these drugs are superior to other classes of antihypertensive agents remains controversial. However, a number of studies have suggested that ACE inhibitors have renoprotective effects inde- pendent of blood pressure reduction. The status of AII antagonists as renoprotective agents is not as well established with several large clinical studies using these agents now in progress.

Renin-Angiotensin System