Role of angiotensin II in the progression of diabetic nephropathy-therapeutic implications.

During the last four decades, the renin–angiotensin system (RAS) has emerged as an important endocrine factor in the chain of physiological blood pressure regulation and water–electrolyte balance, and as a substantial determinant of cardiovascular and renal remodelling. For >20 years it has been established that angiotensinogen is produced in the liver, and is in turn cleaved by the proteolytic enzyme reninreleasing angiotensin I, which is converted to angiotensin II by the converting enzyme (ACE) in the lung and other organs. It is well known that this circulating RAS is suppressed in patients with diabetic nephropathy [1]. A turning point in the research on the RAS was the finding of local tissue-specific RAS in several organs. Such local systems were found not only in glomerular and tubulointerstitial cells of the kidneys but in almost all organs of the human body. Micropuncture studies of the nephron revealed 1000 times higher concentrations of angiotensin II in proximal tubular and interstitial fluid than in systemic blood [2]. What is the role of this local renal RAS systems? Under physiological conditions, the glomerular RAS is a main player in the regulation of glomerular filtration by influencing the resistance predominantly of the vasa efferentia and to a less degree of the vasa afferentia, and by altering the effective filtration surface. The tubulointerstitial RAS is presumed to stimulate sodium and bicarbonate reabsorption in proximal tubules (by activation of the luminal Naþ/Hþ exchanger, basolateral Na/HCO3 – cotransporter and Naþ/Kþ ATPase). Both systems seem to play an important role in the compensatory mechanisms induced by nephron injury. Excessive local angiotensin II concentration increases glomerular permeability by a variety of mechanisms such as a high intraglomerular transmembrane pressure, suppressed synthesis of negatively charged proteoglycans and nephrin, and enhanced synthesis of extracellular matrix components [3]. In proximal renal tubules, exposed to a protein load, increased angiotensin II synthesis induces interstitial fibrosis. There are two main angiotensin II receptors (AT1 and AT2). Both have been cloned and well characterized [3]. Most biological effects of angiotensin II (Figure 1) are mediated by the AT1 receptor via intracellular activation of phospholipase, inhibition of adenylate cyclase and stimulation of tyrosine phosphorylation [4]. The physiological function of the AT2 receptor is not so well elucidated; however, it is generally presumed that its activation antagonizes the effects transduced by AT1 receptor stimulation (Figure 1). Moreover, the existence of a third type of angiotensin family receptor was recognized (AT4). Stimulation of that receptor by angiotensin IV results in increased plasminogen acivator inhibitor-1 (PAI-1) synthesis in proximal tubular and endothelial cells in the kidney [5,6]. The existence of other types of receptors is still postulated.