The effect of SGLT2 inhibitor and HIF-PHI on the podocyte-specific molecules and cytoskeleton of diabetic podocytes

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) have pleiotropic properties that may affect glomerular podocytes. We studied the effects of SGLT2i and HIF-PHI on cultured podocytes and human diabetic kidney disease (DKD) specimens. Methods Cultured human podocytes were treated with high glucose, Dapagliflozin, or Roxadustat. Podocyte-associated molecules levels and morphological changes were assessed. We then studied the kidney biopsy of 5 DKD patients treated with SGLT2i and 5 untreated DKD patients (control group). The distribution patterns of podocyte-associated molecules were assessed. Results In high glucose condition, cultured podocytes had reduced mRNA expression of nephrin, podocalyxin, and synaptopodin, which was restored by treatment with Dapagliflozin, Roxadustat, or both. The corresponding intracellular protein levels were similarly reduced in high glucose and partly restored by Dapagliflozin, Roxadustat, or both. In high glucose condition, podocyte cell bodies were shrunken, and the distribution of nephrin and podocin on cell surface became granular, which were restored to the normal linear pattern when treated with Dapagliflozin, Roxadustat, or both. In high glucose condition, podocalyxin distribution at podocyte apical membrane was disorganized, while the expression of synaptopodin was reduced in the cell processes, with the punctate appearance disrupted; Dapagliflozin, but not Roxadustat, partly restored their normal distribution. In human DKD, the disorganized nephrin, podocin, podocalyxin, and synaptopodin distribution was similar to cultured podocytes, and the disrupted distribution returned to the normal linear continuous pattern with SGLT2i treatment. Conclusion SGLT2i Dapagliflozin and HIF-PHI Roxadustat partly restore the podocyte morphology and intracellular mRNA and protein levels of podocyte-associated molecule in a diabetic milieu. Clinical trial number Not applicable.