Key result
Endothelial ANGPTL4 depletion protects diabetic mice against kidney disease by mitigating c-GAS-STING inflammation.
Why the study?
The cell-specific role of ANGPTL4 in endothelial cells, particularly regarding pathological angiogenesis and diabetic kidney disease, was not well known.
Does endothelial ANGPTL4 depletion prevent pathological angiogenesis and mesenchymal activation in diabetic kidney disease?
Does endothelial ANGPTL4 depletion prevent pathological angiogenesis and mesenchymal activation in diabetic kidney disease?
Endothelial ANGPTL4 depletion protects against diabetic kidney disease by regulating pathogenic angiogenesis, metabolism, and inflammation.
Supports endothelial ANGPTL4 as a therapeutic target in diabetic kidney disease; leaves open translation from mouse models to patients.
The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes.
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Srivastava et al. (2025) studied Diabetic kidney disease. Endothelial ANGPTL4 depletion vs. Control mice was evaluated on Mesenchymal activation, fibrogenesis, pathological neovascularization, and inflammation. Endothelial ANGPTL4 depletion in diabetic mice protected against diabetic kidney disease by stabilizing vessels, improving metabolism, and mitigating c-GAS-STING-mediated inflammation.
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