Protective role for kidney TREM2high macrophages in obesity- and diabetes-induced kidney injury

Ayshwarya Subramanian; Katherine A Vernon; Yiming Zhou; Jamie L Marshall; Maria Alimova; Carlos Arevalo; Fan Zhang; Michal Slyper; Julia Waldman; Monica S Montesinos; Danielle Dionne; Lan T Nguyen; Michael S Cuoco; Dan Dubinsky; Jason Purnell; Keith Keller; Samuel H Sturner; Elizabeth Grinkevich; Ayan Ghoshal; Amanda Kotek; Giorgio Trivioli; Nathan Richoz; Mary B Humphrey; Isabella G Darby; Sarah J Miller; Yingping Xu; Astrid Weins; Alexandra Chloe-Villani; Steven L Chang; Matthias Kretzler; Orit Rosenblatt-Rosen; Jillian L Shaw; Kurt A Zimmerman; Menna R Clatworthy; Aviv Regev; Anna Greka

doi:10.1016/j.celrep.2024.114253

Protective role for kidney TREM2^high macrophages in obesity- and diabetes-induced kidney injury

Cell Rep. 2024 Jun 25;43(6):114253. doi: 10.1016/j.celrep.2024.114253. Epub 2024 May 22.

Authors

Ayshwarya Subramanian¹, Katherine A Vernon², Yiming Zhou³, Jamie L Marshall⁴, Maria Alimova⁵, Carlos Arevalo⁴, Fan Zhang⁶, Michal Slyper⁷, Julia Waldman⁷, Monica S Montesinos², Danielle Dionne², Lan T Nguyen², Michael S Cuoco², Dan Dubinsky⁷, Jason Purnell⁷, Keith Keller⁵, Samuel H Sturner², Elizabeth Grinkevich⁵, Ayan Ghoshal², Amanda Kotek⁸, Giorgio Trivioli⁹, Nathan Richoz¹⁰, Mary B Humphrey¹¹, Isabella G Darby¹¹, Sarah J Miller¹¹, Yingping Xu¹², Astrid Weins¹³, Alexandra Chloe-Villani², Steven L Chang¹⁴, Matthias Kretzler¹⁵, Orit Rosenblatt-Rosen⁷, Jillian L Shaw⁴, Kurt A Zimmerman¹¹, Menna R Clatworthy¹⁶, Aviv Regev¹⁷, Anna Greka¹⁸

Affiliations

¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: as3894@cornell.edu.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: zhouym35@mail.sysu.edu.cn.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK; Nephrology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
¹¹ Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹² Institute of Dermatology and Venereology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
¹³ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁴ Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA; Division of Urology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁵ Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK; Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK; NIHR Cambridge Biomedical Research Center, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Cambridge, UK.
¹⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: agreka@broadinstitute.org.

Abstract

Diabetic kidney disease (DKD), the most common cause of kidney failure, is a frequent complication of diabetes and obesity, and yet to date, treatments to halt its progression are lacking. We analyze kidney single-cell transcriptomic profiles from DKD patients and two DKD mouse models at multiple time points along disease progression-high-fat diet (HFD)-fed mice aged to 90-100 weeks and BTBR ob/ob mice (a genetic model)-and report an expanding population of macrophages with high expression of triggering receptor expressed on myeloid cells 2 (TREM2) in HFD-fed mice. TREM2^high macrophages are enriched in obese and diabetic patients, in contrast to hypertensive patients or healthy controls in an independent validation cohort. Trem2 knockout mice on an HFD have worsening kidney filter damage and increased tubular epithelial cell injury, all signs of worsening DKD. Together, our studies suggest that strategies to enhance kidney TREM2^high macrophages may provide therapeutic benefits for DKD.

Keywords: CP: Immunology; TREM2; diabetic kidney disease; immune; inflammation; macrophage; myeloid; single-cell transcriptomics.

MeSH terms

Animals
Diabetic Nephropathies* / metabolism
Diabetic Nephropathies* / pathology
Diet, High-Fat*
Female
Humans
Kidney* / metabolism
Kidney* / pathology
Macrophages* / metabolism
Male
Membrane Glycoproteins* / genetics
Membrane Glycoproteins* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout*
Obesity* / complications
Obesity* / metabolism
Obesity* / pathology
Receptors, Immunologic* / genetics
Receptors, Immunologic* / metabolism

Substances

Receptors, Immunologic
Membrane Glycoproteins
Trem2 protein, mouse
TREM2 protein, human

Abstract

MeSH terms

Substances

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