RasGRP4 aggravates ischemia-reperfusion injury in diabetic kidneys by mediating communication between macrophages and T cells

Area of Science:

• Nephrology
• Immunology
• Endocrinology

Background:

• Diabetes mellitus (DM) is a significant risk factor for acute kidney injury (AKI).
• Ras guanine nucleotide-releasing protein-4 (RasGRP4) influences immune responses and kidney disease in diabetes.
• The specific role of RasGRP4 in diabetic renal ischemia-reperfusion injury (IRI) requires elucidation.

Purpose of the Study:

• To investigate the precise role and underlying mechanisms of RasGRP4 in diabetic renal IRI.
• To assess the impact of RasGRP4 deficiency on renal dysfunction, fibrosis, and inflammatory cell infiltration in a diabetic IRI model.

Main Methods:

• Diabetic mouse models were established using a high-fat diet and streptozocin (STZ).
• Renal IRI was induced via renal pedicle clamping and reperfusion.
• In vitro studies utilized high glucose and hypoxia-reoxygenation to model cellular inflammatory injury in HK-2 cells.
• RasGRP4 knockout (RasGRP4-KO) and wild-type (WT) mice were compared.

Main Results:

• RasGRP4-KO mice exhibited significantly reduced renal dysfunction and fibrosis compared to WT mice following diabetic IRI.
• A notable decrease in M1 macrophage and Th17 cell infiltration was observed in the kidneys of RasGRP4-KO mice.
• RasGRP4 deletion inhibited M1 macrophage polarization and Th17 cell differentiation, suppressing the IL-17 signaling pathway in vitro.
• Hyperglycemia exacerbated the renal inflammatory state, intensifying the injury.

Conclusions:

• Ras guanine nucleotide-releasing protein-4 (RasGRP4) plays a critical role in exacerbating diabetic renal IRI.
• RasGRP4 promotes inflammatory cascades involving M1 macrophages, CD4+ T cells, and kidney cells, intensifying the inflammatory storm.
• Targeting RasGRP4 may offer a therapeutic strategy for mitigating kidney injury in diabetic patients.