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

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 [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.

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

“…Genetic deletion of Ccl2 (Mcp1) significantly reduced the influx of macrophages to the kidney, lessened tubular cell injury, and reduced cyst growth (15,22). However, the importance of infiltrating macrophages may be model specific because genetic deletion of CCR2, the Ccl2 ligand, did not affect cyst severity in the cpk mouse model (23). Of interest, our recent data also indicate that inhibition of resident macrophage proliferation and accumulation results in a significant reduction in cyst severity (11).…”

Neutrophil-Derived IL-17 Promotes Ventilator-Induced Lung Injury via p38 MAPK/MCP-1 Pathway Activation

“…Macrophage chemoattractant protein-1 (MCP-1), also known as C–C chemokine ligand 2 (CCL2), is an important downstream molecule of p38 MAPK activation that modulates the recruitment of inflammatory cells into damaged organs and tissues ( 20 ). MCP-1 may also exacerbate lung injury in patients with polycystic kidney disease and acute respiratory distress syndrome ( 21 , 22 ).…”

The Tryptophan Metabolizing Enzyme Indoleamine 2,3-Dioxygenase 1 Regulates Polycystic Kidney Disease Progression

“…Similarly, pharmacological inhibition of IDO1 resulted in a selective reduction of resident macrophages and not infiltrating macrophages, whereas genetic loss decreased both populations within the kidney. The data on the contribution of infiltrating macrophages to PKD progression is inconsistent, and a single study suggests that resident macrophages promote cyst 12 growth in a non-orthologous model of PKD (55,57,82). The role of these populations has not been studied in the slowly progressive Pkd1 RC/RC model.…”