Modifiers of the Kidney Response to Activation of the Renin-Angiotensin System: ACE2 and Adiponectin

The renin-angiotensin system (RAS) and the generation of angiotensin II (Ang II) play a central role in promoting kidney disease, but our understanding of the regulation of RAS in the kidney is incomplete. In this context, I examined the interactions between two factors, ACE2 and adiponectin, and the RAS.;ACE2 is a recently discovered homologue of ACE. I studied the impact of ACE2 gene deletion on the early phase of inflammation in ischemia-reperfusion (I/R) injury when the RAS is activated. ACE2-/- mice exhibited a marked increase in the inflammatory response, cellular apoptosis and oxidative stress to renal I/R injury. These findings show that ACE2 is an important determinant of I/R injury, a model of acute kidney injury.;Adiponectin is produced by adipocytes and its circulating levels decline in obesity. I studied direct interactions between Ang II and adiponectin on cell signaling and activation of NADPH oxidase activity. The rationale for this study is based on the recognition that obesity is an emerging epidemic and it is associated with both increased risk for chronic kidney disease (CKD) and reduced levels of adiponectin. Kidney tubular cells expressed adiponectin receptors and adipoR1-mediated activations of AMPK and cAMP-Epac signaling attenuated Ang II-induced NADPH oxidase activity, NFkappaB activation, and fibronectin expression. These findings show that adiponectin can protect kidney cells, and that obesity-associated declines in circulating adiponectin may contribute to the link between CKD progression and obesity.;Diabetic nephropathy (DN) is also associated with activation of the RAS. I therefore studied the impact of adiponectin gene deletion on the development of DN. Adiponectin-/- mice with diabetes exhibited an exaggerated renal hypertrophic response and more severe albuminuria. Glomerular injury was also greater in the adiponectin-/- mice with diabetes. Deletion of the gene for adiponectin led to increased alphaSMA expression, collagen IV deposition, and macrophage infiltration in the kidney. In vitro studies showed that adiponectin inhibited high glucose-induced activation of mTOR, TGF-beta1, NFkappaB, and NADPH oxidase in glomerular mesangial cells. These findings show that adiponectin modulates the kidney response to high glucose both in vivo and in vitro.;In summary, my studies show that ACE2 and adiponectin are important determinants of kidney injury, at least in part due to their effects on Ang II and high glucose in the kidney.