PMID- 30209078 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20191001 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 29 IP - 10 DP - 2018 Oct TI - Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease. PG - 2471-2481 LID - 10.1681/ASN.2018050518 [doi] AB - BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), most of whom have a mutation in PKD1 or PKD2, abnormally large numbers of macrophages accumulate around kidney cysts and promote their growth. Research by us and others has suggested that monocyte chemoattractant protein-1 (Mcp1) may be a signal for macrophage-mediated cyst growth. METHODS: To define the role of Mcp1 and macrophages in promoting cyst growth, we used mice with inducible knockout of Pkd1 alone (single knockout) or knockout of both Pkd1 and Mcp1 (double knockout) in the murine renal tubule. Levels of Mcp1 RNA expression were measured in single-knockout mice and controls. RESULTS: In single-knockout mice, upregulation of Mcp1 precedes macrophage infiltration. Macrophages accumulating around nascent cysts (0-2 weeks after induction) are initially proinflammatory and induce tubular cell injury with morphologic flattening, oxidative DNA damage, and proliferation-independent cystic dilation. At 2-6 weeks after induction, macrophages switch to an alternative activation phenotype and promote further cyst growth because of an additional three-fold increase in tubular cell proliferative rates. In double-knockout mice, there is a marked reduction in Mcp1 expression and macrophage numbers, resulting in less initial tubular cell injury, slower cyst growth, and improved renal function. Treatment of single-knockout mice with an inhibitor to the Mcp1 receptor Ccr2 partially reproduced the morphologic and functional improvement seen with Mcp1 knockout. CONCLUSIONS: Mcp1 is upregulated after knockout of Pkd1 and promotes macrophage accumulation and cyst growth via both proliferation-independent and proliferation-dependent mechanisms in this orthologous mouse model of ADPKD. CI - Copyright (c) 2018 by the American Society of Nephrology. FAU - Cassini, Marcelo F AU - Cassini MF AD - Section of Nephrology, Department of Medicine. FAU - Kakade, Vijayakumar R AU - Kakade VR AD - Section of Nephrology, Department of Medicine. FAU - Kurtz, Elizabeth AU - Kurtz E AD - Section of Nephrology, Department of Medicine. FAU - Sulkowski, Parker AU - Sulkowski P AD - Department of Genetics. AD - Department of Therapeutic Radiology, and. FAU - Glazer, Peter AU - Glazer P AD - Department of Genetics. AD - Department of Therapeutic Radiology, and. FAU - Torres, Richard AU - Torres R AD - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut. FAU - Somlo, Stefan AU - Somlo S AD - Section of Nephrology, Department of Medicine. FAU - Cantley, Lloyd G AU - Cantley LG AD - Section of Nephrology, Department of Medicine, lloyd.cantley@yale.edu. LA - eng GR - R01 DK054053/DK/NIDDK NIH HHS/United States GR - T32 HD007149/HD/NICHD NIH HHS/United States GR - P30 DK079310/DK/NIDDK NIH HHS/United States GR - R01 DK099504/DK/NIDDK NIH HHS/United States GR - R01 DK100592/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180912 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (INCB3344) RN - 0 (Pyrrolidines) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, CCR2) RN - 0 (TRPP Cation Channels) RN - 0 (polycystic kidney disease 1 protein) SB - IM CIN - J Am Soc Nephrol. 2018 Oct;29(10):2447-2448. PMID: 30209077 MH - Animals MH - Chemokine CCL2/deficiency/*genetics/*physiology MH - DNA Damage MH - Disease Models, Animal MH - Humans MH - Kidney Tubules/pathology/physiopathology MH - Macrophage Activation/drug effects/genetics/physiology MH - Macrophages/drug effects/pathology/*physiology MH - Male MH - Mice MH - Mice, Knockout MH - Polycystic Kidney, Autosomal Dominant/*genetics/*pathology/physiopathology MH - Pyrrolidines/pharmacology MH - Reactive Oxygen Species/metabolism MH - Receptors, CCR2/antagonists & inhibitors MH - TRPP Cation Channels/deficiency/genetics MH - Up-Regulation PMC - PMC6171277 OTO - NOTNLM OT - ADPKD OT - Immunology and pathology OT - MCP-1 OT - genetic renal disease OT - kidney tubule OT - polycystic kidney disease EDAT- 2018/09/14 06:00 MHDA- 2019/09/17 06:00 PMCR- 2019/10/01 CRDT- 2018/09/14 06:00 PHST- 2018/05/17 00:00 [received] PHST- 2018/07/27 00:00 [accepted] PHST- 2018/09/14 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/09/14 06:00 [entrez] PHST- 2019/10/01 00:00 [pmc-release] AID - ASN.2018050518 [pii] AID - 2018050518 [pii] AID - 10.1681/ASN.2018050518 [doi] PST - ppublish SO - J Am Soc Nephrol. 2018 Oct;29(10):2471-2481. doi: 10.1681/ASN.2018050518. Epub 2018 Sep 12.