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

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 I angiotensin (AT(1)) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Fas(lpr/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 I 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.