The importance of the intrarenal renin–angiotensin system

Virtually every organ system in the human body seems to possess a local renin–angiotensin system (RAS). Most of these systems are independently regulated and compartmentalized from the plasma circulation. In this Review, Velez focuses on the kidney RAS, which is of critical importance for the regulation of blood pressure and salt balance. The article integrates the traditional understanding of the intrarenal RAS with the emerging role of novel players in the system, and the potential implications of these factors in the mechanisms of tissue injury in progressive chronic kidney diseases. Evidence suggests that virtually every organ system in the human body possesses a local renin–angiotensin system (RAS). These local systems seem to be independently regulated and compartmentalized from the plasma circulation, perhaps with the exception of the vascular endothelial system, which is responsible for maintaining physiological plasma levels of RAS components. Among these local RASs, the kidney RAS—the focus of this Review—seems to be of critical importance for the regulation of blood pressure and salt balance. Indeed, overactivation of the intrarenal RAS in certain disease states constitutes a pathogenic mechanism that leads to tissue injury, proliferation, fibrosis and ultimately, end-organ damage. Intrarenal levels of angiotensin peptides are considerably higher than those in plasma or any other organ tissue. Moreover, the kidney has a unique capacity to degrade angiotensin peptides, perhaps to maintain its intrinsic homeostasis. Interestingly, each local RAS has a distinct enzymatic profile resulting in different patterns of angiotensin fragment generation in different tissues. A better understanding of the autocrine and paracrine mechanisms involved in the renal RAS and other local RASs might direct future organ-specific therapy. Key Points Intrarenal levels of angiotensin II and other angiotensin peptides are considerably higher than those in plasma; both glomerular and tubular compartments of the kidney possess an intrinsic local renin–angiotensin system Upregulation of the intrarenal renin–angiotensin system has been linked with the pathogenesis of various models of proteinuric kidney diseases including diabetic and hypertensive glomerulopathies Intrarenal angiotensin-converting enzyme 2 activity seems to counterbalance the actions of angiotensin-converting enzyme by converting angiotensin II to angiotensin-(1–7), a peptide that primarily antagonizes the a