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

TL;DR

This study shows that SGLT2 inhibitors and HIF-PHI drugs can help restore damaged kidney podocytes in diabetes, but combining them doesn't add extra benefits.

Contribution

Demonstrates that SGLT2i and HIF-PHI can restore podocyte structure and function in diabetic conditions, with no added benefit from combining both.

Findings

SGLT2i and HIF-PHI restored mRNA and protein levels of podocyte-specific molecules in high glucose conditions.

Podocyte morphology and molecule distribution in diabetic kidney biopsies improved with SGLT2i treatment.

Combining SGLT2i and HIF-PHI did not provide additional benefits over using either drug alone.

Abstract

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.

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.

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.

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.

Not applicable.

The online version contains supplementary material available at 10.1186/s12882-025-04677-0.

What was known

This study adds

Potential impact

• Podocyte dysfunction plays an important role in the pathogenesis of diabetic kidney disease (DKD)

• Sodium-glucose cotransporter 2 (SGLT2) inhibitors and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) have pleiotropic properties on glomerular podocytes.

• In cultured human podocytes, SGLT2i and HIF-PHI partly restore the podocyte morphology and intracellular mRNA and protein levels of podocyte-associated molecules in a diabetic milieu.

• The same pattern of podocyte-associated molecules changes was present in kidney biopsy from DKD patients with SGLT2i treatment.

• Our study showed that SGLT2 inhibitor and HIF-PH inhibitor are protective to podocytes in vitro, but the concomitant use of these two medications does not appear to have obvious additional effects.

The online version contains supplementary material available at 10.1186/s12882-025-04677-0.

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