Kidney angiopoietin-like protein 4 regulates fibrotic responses in diabetic kidney disease

The angiopoietin-like (ANGPTL) proteins are now recognized as critical regulators of the harmful changes seen in diabetic kidney disease. Notably, a hyposialylated pro-proteinuric form of ANGPTL4 has been identified as a crucial contributor to fibrosis within diabetic kidneys. Under diabetic conditions, glomerular podocytes secrete this hyposialylated ANGPTL4, which plays a significant role in disrupting lipid metabolism, promoting inflammation, and driving fibrosis in both podocytes and adjacent tubules. This secreted ANGPTL4 interacts with tubular cells via Integrin-1 and DPP-4, causing mitochondrial damage that activates the c-GAS-STING pathway and exacerbates inflammation. Importantly, targeting renal ANGPTL4 with antisense oligonucleotides (ASOs) has shown promising protective effects against fibrosis in diabetic kidneys, paving the way for innovative therapeutic strategies to combat diabetic kidney disease and other fibrotic disorders.