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. 2023 Aug 25;46(9):1574–1586. doi: 10.2337/dci23-0030

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© 2023 by the American Diabetes Association

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Local mechanisms underlying glomerular hypertension. Endothelin 1, reactive oxygen species, and thromboxane A2 increase efferent vessel tone, whereas insulin resistance upregulates cyclooxygenase 2 (COX-2), prostanoids, and the kallikrein-kinin system, resulting in afferent arteriole dilatation (138). RAS activation damages glomerular endothelial cells (GEC), which increases fenestrations and induces apoptosis. Hyperglycemia leads to advanced glycation end products (AGEs), which bind to their receptors (RAGEs), which decreases nitric oxide (NO) availability and stimulates transforming growth factor-β (TGF-β), a profibrotic factor. Diabetes further accelerates endothelial progenitor cell (EPC) aging, which reduces their reparative function. Vascular endothelial growth factor (VEGF) synthesis by podocytes is dysregulated. Podocyte injury leads to foot process effacement and podocyte loss, the unifying mechanism underlying albuminuria in diabetes (33–37).