The Journal of Clinical Investigation. 2009 Apr;119(4):943-53. doi: 10.1172/JCI34862. Epub 2009 Mar 16.

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

Significance:

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of autoimmune glomerular diseases and that blockade of the RAS has beneficial effects. MRL/MpJ-Faslpr/lpr (lpr) mice develop florid autoimmune disease resembling human SLE which is modulated by angiotensin-converting enzyme (ACE) inhibitors or AT₁ receptor blockers. In this study a genetic approach was taken to investigate the role of AT₁ receptors in the development of autoimmune disease. To this end, a lpr mouse line deficient in the major murine AT₁ receptor, AT1A was generated. Surprisingly, we found enhanced mortality and more aggressive kidney disease in lpr mice lacking AT_1A receptors. This acceleration of renal disease is caused by activation of glomerular AT_1B receptors. These experiments therefore demonstrate that activation of AT₁ receptors in the glomerulus can directly promote inflammatory injury in the kidney independent of elevated blood pressure.

Abstract:

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT₁) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT_1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT_1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT_1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT_1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT_1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT_1A-deficient lpr mice, and they showed evidence of exaggerated AT_1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT_1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.