biostudies-literatureZhang LScientific Research Program of Tianjin Education CommissionScientific Research Funding of Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Key Laboratory of Metabolic DiseasesNational Natural Science Foundation of ChinaBethune Charitable FoundationHubei Chen Xiaoping Science and Technology Development FundChina Endocrine Metabolism Talent Research FundTianjin Key Medical Discipline (Specialty) Construction Projecte187653https://www.ebi.ac.uk/biostudies/studies/S-EPMC11790033biostudies-literatureUnknown10(2)Diabetes mellitus (DM) is acknowledged as an independent risk factor for acute kidney injury. Ras guanine nucleotide-releasing protein-4 (RasGRP4) exerts a notable role in modulating immune-inflammatory responses and kidney disease progression in diabetes. Herein, we delved into the specific role and mechanism of RasGRP4 in diabetic renal ischemia-reperfusion injury. Diabetes was induced by a high-fat diet and streptozocin (STZ) injections, followed by creating an ischemia-reperfusion kidney injury via renal pedicle clamping and reperfusion. In vitro, a high glucose and hypoxia-reoxygenation modeled cellular inflammatory injury. We found RasGRP4-KO mice, compared with C57BL/6J (WT) mice, showed markedly less renal dysfunction and fibrosis in diabetic ischemia-reperfusion injury. There was JCI insightRasGRP4 aggravates ischemia-reperfusion injury in diabetic kidneys by mediating communication between macrophages and T cells.PMC117900332022-N-02-07,2023-N-03-15ZXY-ZDSYSZD2022-1Z04JKM2022E035TJYXZDXK-032A2022KJ248CXPJJH122012-00281600643Yu PZhou SZhang LChen SWang ZZhang BWu YMeng XfalseRasGRP4 aggravates ischemia-reperfusion injury in diabetic kidneys by mediating communication between macrophages and T cells.Diabetes mellitus (DM) is acknowledged as an independent risk factor for acute kidney injury. Ras guanine nucleotide-releasing protein-4 (RasGRP4) exerts a notable role in modulating immune-inflammatory responses and kidney disease progression in diabetes. Herein, we delved into the specific role and mechanism of RasGRP4 in diabetic renal ischemia-reperfusion injury. Diabetes was induced by a high-fat diet and streptozocin (STZ) injections, followed by creating an ischemia-reperfusion kidney injury via renal pedicle clamping and reperfusion. In vitro, a high glucose and hypoxia-reoxygenation modeled cellular inflammatory injury. We found RasGRP4-KO mice, compared with C57BL/6J (WT) mice, showed markedly less renal dysfunction and fibrosis in diabetic ischemia-reperfusion injury. There was 2024-01-01T00:00:00Z2024 Dec2025-04-19T16:24:19.041Z2025-04-19T16:24:19.041ZS-EPMC117900333965654210.1172/jci.insight.187653