| Autor: |
Salah SM; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Meisenheimer JD; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Rao R; Department of Internal Medicine-Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Peda JD; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Wallace DP; Department of Internal Medicine-Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas.; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Foster D; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Li X; Department of Internal Medicine-Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas., Li X; Department of Internal Medicine-Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Zhou X; Department of Internal Medicine-Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Vallejo JA; Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.; Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri., Wacker MJ; Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri., Fields TA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Swenson-Fields KI; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas. |
| Abstrakt: |
Polycystic kidney disease (PKD) is characterized by slowly expanding renal cysts that damage the kidney, typically resulting in renal failure by the fifth decade. The most common cause of death in these patients, however, is cardiovascular disease. Expanding cysts in PKD induce chronic kidney injury that is accompanied by immune cell infiltration, including macrophages, which we and others have shown can promote disease progression in PKD mouse models. Here, we show that monocyte chemoattractant protein-1 [MCP-1/chemokine (C-C motif) ligand 2 (CCL2)] is responsible for the majority of monocyte chemoattractant activity produced by renal PKD cells from both mice and humans. To test whether the absence of MCP-1 lowers renal macrophage concentration and slows disease progression, we generated genetic knockout (KO) of MCP-1 in a mouse model of PKD [congenital polycystic kidney ( cpk ) mice]. Cpk mice are born with rapidly expanding renal cysts, accompanied by a decline in kidney function and death by postnatal day 21 . Here, we report that KO of MCP-1 in these mice increased survival, with some mice living past 3 mo. Surprisingly, however, there was no significant difference in renal macrophage concentration, nor was there improvement in cystic disease or kidney function. Examination of mice revealed cardiac hypertrophy in cpk mice, and measurement of cardiac electrical activity via ECG revealed repolarization abnormalities. MCP-1 KO did not affect the number of cardiac macrophages, nor did it alleviate the cardiac aberrancies. However, MCP-1 KO did prevent the development of pulmonary edema, which occurred in cpk mice, and promoted decreased resting heart rate and increased heart rate variability in both cpk and noncystic mice. These data suggest that in this mouse model of PKD, MCP-1 altered cardiac/pulmonary function and promoted death outside of its role as a macrophage chemoattractant. |
