Obesity is a risk factor for chronic as well as acute kidney injury (AKI). Chronic kidney injury arises as a result of progressive loss of kidney function leading to irreversible damage, while AKI occurs as an abrupt loss of kidney function and usually is reversible. In both processes, inflammation plays an important role in the initiation and maintenance of the injury. Renal inflammation is influenced by an interplay of pro- and anti- inflammatory cytokines released by kidney cells and macrophages (broadly defined M1 and M2 types). While M1 type are pro-inflammatory and cause renal injury (chronic and acute), M2 are anti-inflammatory and help repair post AKI during the recovery phase. Thus altering the interplay between kidney cells and macrophages offers a potential novel target to combat local inflammation and protect the kidney from chronic as well acute injury. Recently, we and others have revealed that angiotensin type 2 receptors (AT2R) exert anti-inflammatory and reno-protective actions, novel functions of AT2R in addition to natriuresis and blood pressure regulation. Our preliminary studies in pre-hypertensive obese rat and mice suggest that AT2R agonist treatment reduces inflammatory cytokines and protects against chronic kidney injury as well as AKI. A series of in vitro experiments in human kidney proximal tubule epithelial cells (HK-2) and macrophages (THP-1 cells) revealed that AT2R activation increases IL-10, which may be critical pathway in reducing pro-inflammatory cytokines and creating a cross-talk between proximal tubules and macrophages, including shifting macrophages from M1 to M2 type. These studies provide a strong premise to hypothesize that AT2R activation promotes a cross-talk (interplay) between kidney epithelial cells and macrophages, via the anti-inflammatory IL-10 pathway, preventing chronic and acute kidney injury in obesity. Moreover, AT2R shifts the macrophage balance between M1 and M2 types limiting kidney injury and promoting repair, particularly in AKI in obesity. To test this hypothesis, Aim 1 is directed to determine that renal AT2R via IL-10 pathway reduces local inflammation and protects kidney against chronic injury in obesity.
Aim 2 will study that AT2R activation attenuates AKI and promotes kidney repair via a macrophage polarity shift towards M2 type. Uninephrectomized obese Zucker rats will be used and placed on normal saline for chronic kidney injury and subjected to ischemia/reperfusion (I/R) for AKI. Kidney specific knockdown of AT2R and IL-10 will achieved by utilizing shRNA plasmid DNA encapsulated in microbubble technology, to study the role of kidney AT2R and IL-10 in reno-protection, anti- inflammation and kidney repair. To define AT2R gender bias, experiments to study the role of estrogen in AT2R-mediated reno-protection in females have been included. State-of-the-art techniques will be employed to determine biochemical, histological and molecular outcomes of kidney injury and function. The proposed studies will elucidate the novel role of the kidney AT2R in reno-protection and identify it as a novel therapeutic target for preventing and repairing kidney injury.
Obesity/diabetes is a major health problem in the United States, and a risk factor for kidney chronic and acute injury. We propose to investigate the role/mechanisms of a novel target, namely the Angiotensin II AT2 receptor, to protect kidney structure and function against injury in obese animal models.
