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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. [Display omitted] • TREM2 high macrophages reside in the human adult kidney • Trem2 high macrophages increase in frequency in a high-fat-diet mouse model of diabetic kidney disease • Human adult diabetic and obese kidney tissue has increased frequency of TREM2 high macrophages • Trem2 deletion promotes kidney injury after exposure to a high-fat diet but not a regular diet Subramanian et al. identify a macrophage population expressing a TREM2 high transcriptional program in the human adult kidney, matching a homologous population in other tissues (adipose, heart, and liver). Trem2 high macrophages expand in diabetic kidney disease in both a high-fat-diet-fed mouse model and an independent cohort of patients. Trem2 deletion results in hastened kidney injury in the presence of a high-fat diet, suggesting a role of these macrophages as responders to local tissue injury in obesity- and diabetes-driven kidney injury. [ABSTRACT FROM AUTHOR]