MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease

Sally M. Salah, James D. Meisenheimer, Reena Rao, Jacqueline D. Peda, Darren P. Wallace, Dawson Foster, Xiaogang Li, Xiaoyan Li, Xia Zhou, Julian A. Vallejo, Michael J. Wacker, Timothy A. Fields, Katherine I. Swenson-Fields

Research output: Contribution to journalArticle

Abstract

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 [con-genital 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.

Original languageEnglish (US)
Pages (from-to)F343-F360
JournalAmerican Journal of Physiology - Renal Physiology
Volume317
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Polycystic Kidney Diseases
Pulmonary Edema
Kidney
Macrophages
Cysts
Chemokine CCL2
Chemotactic Factors
Disease Progression
Heart Rate
Cystic Kidney Diseases
Cardiomegaly
Renal Insufficiency
Monocytes
Cause of Death
Electrocardiography
Cardiovascular Diseases

Keywords

  • Cardiovascular disease
  • Cpk mice
  • Monocyte chemoattractant protein-1
  • Polycystic kidney disease

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Salah, S. M., Meisenheimer, J. D., Rao, R., Peda, J. D., Wallace, D. P., Foster, D., ... Swenson-Fields, K. I. (2019). MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease. American Journal of Physiology - Renal Physiology, 317(2), F343-F360. https://doi.org/10.1152/ajprenal.00240.2018

MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease. / Salah, Sally M.; Meisenheimer, James D.; Rao, Reena; Peda, Jacqueline D.; Wallace, Darren P.; Foster, Dawson; Li, Xiaogang; Li, Xiaoyan; Zhou, Xia; Vallejo, Julian A.; Wacker, Michael J.; Fields, Timothy A.; Swenson-Fields, Katherine I.

In: American Journal of Physiology - Renal Physiology, Vol. 317, No. 2, 01.01.2019, p. F343-F360.

Research output: Contribution to journalArticle

Salah, SM, Meisenheimer, JD, Rao, R, Peda, JD, Wallace, DP, Foster, D, Li, X, Li, X, Zhou, X, Vallejo, JA, Wacker, MJ, Fields, TA & Swenson-Fields, KI 2019, 'MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease', American Journal of Physiology - Renal Physiology, vol. 317, no. 2, pp. F343-F360. https://doi.org/10.1152/ajprenal.00240.2018
Salah, Sally M. ; Meisenheimer, James D. ; Rao, Reena ; Peda, Jacqueline D. ; Wallace, Darren P. ; Foster, Dawson ; Li, Xiaogang ; Li, Xiaoyan ; Zhou, Xia ; Vallejo, Julian A. ; Wacker, Michael J. ; Fields, Timothy A. ; Swenson-Fields, Katherine I. / MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease. In: American Journal of Physiology - Renal Physiology. 2019 ; Vol. 317, No. 2. pp. F343-F360.
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abstract = "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 [con-genital 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.",
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