{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:38:57Z","timestamp":1793036337418,"version":"4.5.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"abstract":"\n Key Points<\/jats:title>\n \n \n \n Triggering receptor expressed on myeloid cells 2 deficiency worsened albuminuria, lowered GFR, and aggravated glomerular and tubular injury in diabetic mice.<\/jats:p>\n <\/jats:list-item>\n \n Triggering receptor expressed on myeloid cells 2 was induced in resident-associated macrophages in the glomerular niche and monocyte-derived macrophages in the tubulointerstitium.<\/jats:p>\n <\/jats:list-item>\n \n Bone marrow chimeras showed that resident triggering receptor expressed on myeloid cells 2 protected the glomerulus, whereas donor-derived triggering receptor expressed on myeloid cells 2 limited tubulointerstitial injury.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Diabetic kidney disease (DKD) is driven by complex pathologic mechanisms including lipid accumulation, chronic inflammation, and fibrosis, contributing to progressive kidney dysfunction. Macrophages are key contributors to DKD pathogenesis, yet their functional heterogeneity in the diabetic kidney remains poorly defined. Although triggering receptor expressed on myeloid cells 2 (TREM2\n +<\/jats:sup>\n ) macrophages have been identified within the diabetic microenvironment, the relationship between their developmental origin, anatomic localization, and functional specialization remains unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study, we integrated single-cell RNA sequencing, spatial transcriptomic analysis of diabetic OVE26 kidneys, and reciprocal bone marrow transplantation in a high-fat diet plus streptozotocin-induced diabetic model to examine how TREM2\n +<\/jats:sup>\n macrophages are distributed across renal compartments and how TREM2 deficiency affects DKD injury.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Global TREM2 deficiency markedly exacerbated tubulointerstitial injury and glomerular hypertrophy in DKD, establishing TREM2 as a protective factor. Single-cell RNA sequencing and spatial mapping revealed that TREM2 induction in diabetic kidneys occurs in 2 spatially distinct macrophage populations: Mrc1\n +<\/jats:sup>\n kidney-resident macrophages localized to the periglomerular niche and Ccr2\n +<\/jats:sup>\n monocyte-derived macrophages infiltrating the tubulointerstitium. Transcriptomic and functional analyses were consistent with a role of TREM2 in macrophage phagocytic and lipid-handling programs. Its loss led to the downregulation of phagosome and endocytic pathways, resulting in failed clearance of apoptotic debris and lipid aggregates, which was particularly pronounced in the tubulointerstitium. Reciprocal bone marrow transplant experiments suggest that recipient-resident TREM2 was more associated with preservation of glomerular structure, whereas donor-derived hematopoietic TREM2 was more strongly associated with limiting tubular lipid accumulation, apoptotic tubular epithelial cells, and tubulointerstitial injury.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings suggested that TREM2-expressing macrophages contributed to compartment-specific protective responses in DKD. TREM2 deficiency was associated with greater diabetic glomerular and tubular injury, with distinct phenotypes observed in donor hematopoietic and recipient compartments.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000001248","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:00:50Z","timestamp":1789401650000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Spatially Distinct Triggering Receptor Expressed on Myeloid Cells 2+ Macrophages Are Associated with Compartment-Specific Protection in Diabetic Kidney Disease"],"prefix":"10.1681","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-3813","authenticated-orcid":false,"given":"Jia","family":"Fu","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3353-7245","authenticated-orcid":false,"given":"Yangyang","family":"Niu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-2284","authenticated-orcid":false,"given":"Zeguo","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0803-109X","authenticated-orcid":false,"given":"Benjamin","family":"Lo","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8659-1092","authenticated-orcid":false,"given":"Jessica","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8078-7605","authenticated-orcid":false,"given":"Wei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9756-1765","authenticated-orcid":false,"given":"Kyung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1502-2849","authenticated-orcid":false,"given":"John Cijiang","family":"He","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York"},{"name":"Renal Program, James J. 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