Angiotensin AT1 and AT2 receptors the battle for health and disease

Proteinuria is associated with progression to end stage renal disease. The exact mechanisms contributing to the development of this pathological condition are yet to be elucidated. In the June issue of the American Journal of Pathology , Suzuki et al. [ 1 ] investigated the role of angiotensin II (Ang II) type 1 (AT1) and type 2 (AT2) receptors in regulating the barrier functions of the slit diaphragm, a component of a filtration barrier of the kidney glomerulus, which prevent the leak of plasma proteins into urine. Both in vivo and in vitro studies were performed in female Brown Norway rats and in immortalized mouse podocytes. Rats developed proteinuria by the induction of nephropathy post-anti-nephrin antibody (ANA) administration. The development of nephropathy was based on ANA down-regulation of the slit diaphragm functional molecules. In this animal model, there was an increase in the expression of AT1 and AT2 receptors together with a decreased expression of nephrin, podocin and ZO-1. These results were supported by the increase in the copy number of AT1 and AT2 receptors' mRNA. Importantly, these changes correlated with the proteinuric state. The expression of the glomerular AT1 and AT2 receptors was localized mainly in the podocytes. AT1 receptor blockade ameliorated the proteinuria caused by a reduction in the functional molecules of slit diaphragm, mainly the reduction of nephrin and podocin. Although AT2 receptor blockade did not influence these proteins, stimulation of the AT2 receptor enhanced their expressions. These results were confirmed in cultured podocytes, where Ang II reduced nephrin mRNA, an effect that was reversed by AT1 receptor blockade and AT2 receptor stimulation. The fact that animals lacking the AT2 receptor do not develop nephropathy positions the AT1 receptor as the primary receptor that contributes to the development of kidney disease. It would be interesting to repeat these studies in the AT2 receptor knockout mice and evaluate whether these animals are more susceptible to the development of this type of nephropathy. It is possible that AT2 receptor protective function is induced when there is a renal injury and this effect would not be necessary obvious in absence of renal pathology. These results demonstrate the potential for the development of a new therapy to treat proteinuria based on AT2 receptor stimulation. Structurally glomerular endothelial cells, glomerular basement membranes (GBM) and podocyte foot processes form glomerular capillary wall. Glomerular slit diaphragm is a membrane-like structure that connects foot processes of different cells including podocytes and functions as a barrier that prevents leakage of plasma proteins into urine. Several molecules were described as components and regulators of the functions of the slit diaphragm, mainly nephrin, podocin and CD2-associated protein. Ang II is involved in the development of kidney diseases, leading to increased morbidity and mortality. Past studies have provided convincing evidence that interruption of the renin–angiotensin system (RAS) through the use of angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor blockers improve the renal outcome [ 2–10 ]. The exact mechanism of the contribution of the RAS to the development of kidney disease is not well-established. All components of the RAS are present in the kidney [ 11 ]. The concentration of Ang II in the renal proximal tubules and interstitial fluid is approximately 1000 times the concentration in plasma. Angiotensin receptor subtypes AT1 and AT2 have also been localized in the kidney [ 12 ]. Angiotensin AT1 receptors are present in the renal vasculature, glomerular mesangium, interstitial cells and proximal tubules, while AT2 receptors have been localized at the renal vessels, glomeruli and tubules. AT1 receptor, a G-protein coupled receptor, is the principal Ang II receptor and is linked to the development of a variety of renal and cardiovascular diseases. It is well-established that AT1 contributes to such pathological conditions by the stimulation of cellular growth via protein phosphorylation, which in turn activates DNA transcription of several cytokines and growth mediators such as TNFα and TGF-β. Unlike AT1 receptor, the AT2 receptor is coupled to various phosphatases and mediates protein dephosphorylation. AT2 receptor has several described functions related to the inhibition of cell growth, promotion of cell differentiation, and stimulation of apoptosis [ 10 ]. In addition, AT2 receptor stimulates the renal production of NO, bradykinin and cGMP [ 13–16 ]. Although it is known that the AT1 receptor may contribute to the development of kidney diseases, the mechanisms that lead to these pathological conditions are not well understood. Furthermore, it is not known if AT2 receptor plays any role in these diseases. Similarly, the available data are not clear on the events that mediate the development of nephropathy, in particular the changes that are mediated by Ang II. Ang II stimulates bioactivation and expression of TGF-β leading to renal hypertrophy and accumulation of extracellular matrix proteins in the kidney. Similarly, cytokines, including TNFα, have been implicated in the development and progression of nephropathy. TNFα is stimulated by Ang II and leads to the development of renal fibrosis [ 17 ]. A study by Suzuki et al. [ 1 ] reports of an increased Ang II production in animals treated with ANA and a developed reduction in slit diaphragm functional molecules leading to proteinuria. The mechanism involved in this process is mediated by AT1 receptor, since its blockade restored the slit diaphragm functional proteins and reduced the proteinuria. Is there a role for the AT2 receptor in improving this pathological process? It is well-established that AT2 receptor inhibits cell proliferation and matrix formation [ 11 ]. However, despite the availability of this information, the potential therapeutic role of the AT2 receptor in nephropathy is unknown. Previous studies demonstrated protective renal effects for the AT2 receptors through enhancing renal vasodilation [ 18 ] and sodium excretion [ 15 ]. Thus, renal localization of the AT2 receptor may determine its mechanisms that are involved in preventing the development of kidney diseases. Presence of the AT2 receptors in podocytes [ 1 ] suggest their involvement in the regulation of slit diaphragm functional molecules. This effect is confirmed by the observation of enhanced expression of nephrin and podocin during AT2 receptor stimulation. Thus, restoration of AT2 receptor activity may protect against the development of renal morphologic and functional changes seen during the development of nephropathy. Similarly, stimulation of the AT2 receptor may be a potential new therapeutic option for the management of renal diseases, in particular with the recent evidence that this receptor inhibits renin biosynthesis [ 19 , 20 ] and leads to a down-regulation of the RAS activity. Additionally, the potential use of multiple blockers of RAS such as AT1 receptor blockers and angiotensin converting enzyme or direct renin inhibitors may add more therapeutic efficacy to the management of kidney diseases. A recent study [ 21 ] suggests that the combination of the renin inhibitor, aliskiren and the AT1 receptor blocker valsartan, at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent. This study was supported by grant DK078757 and HL091535 from the National Institutes of Health to H. M. S., MD. Dr Siragy was the recipient of the Research Career Development Award K04-HL-03006 from the National Institutes of Health. Conflict of interest statement . None declared.