Abstract 15686: Renal Collecting Duct Epithelial Cells Regulate Inflammation in Chronic Kidney Disease and Cardiorenal Interactions
Chronic kidney disease (CKD) is a significant risk factor for cardiovascular disease. However, the molecular mechanisms underlying its development and cardiorenal interactions are insufficiently understood. We found that the transcription factor KLF5 is mainly expressed in collecting duct epithelial cells and that the collecting duct-specific deletion of Klf5 (CDKlf5KO) ameliorated the renal injury induced by unilateral ureteral obstruction (UUO), a model CKD. In response to UUO, KLF5 rapidly induces expression of S100A8 and S100A9, which recruit inflammatory monocytes to kidneys and promote their activation into M1-type macrophages, which promote renal epithelial injury and inflammation. Thereafter, the numbers of M2-type macrophages, which promote fibrosis, gradually increase. Because KLF5 regulates early accumulation of CD11b+Ly-6Clow cells in UUO kidneys, Klf5 haploinsufficiency and collecting duct-specific Klf5 deletion skewed macrophage differentiation toward M2, leading to amelioration of the renal injury but enhancement of the fibrosis. Our results demonstrate that KLF5 is a pivotal regulator of the response of collecting duct cells to renal injury. To further analyze the role of KLF5 in cardiorenal interactions, we infused angiotensin II into CDKlf5KO. Blood pressure elevation was not affected by Klf5 deletion. However, approximately 60% of CDKlf5KO mice died within 7 days of Ang II infusion, while no wild-type mice infused with Ang II died. We found that the major cause of death was the rupture of aortic aneurysms. In aortas of CDKlf5KO mice inflammatory cell infiltration was markedly augmented and levels of MMP expression were increased as compared with wild-type mice, showing that the response of renal collecting duct cells to Ang II, which is regulated by KLF5, affects inflammatory processes in the aorta. Our results suggest that the kidney is a vital component in inflammatory regulation of the cardiovascular systems.
- © 2011 by American Heart Association, Inc.