Samaan_2023_Biomed.Pharmacother_167_115629

RATIONALE: Renal hypoxia is one of the currently highlighted pathophysiologic mechanisms of diabetic nephropathy (DN). Both hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha are major regulators of renal adaptive responses to hypoxia. OBJECTIVES: This study aims to compare the effects of vildagliptin (a dipeptidyl peptidase-IV inhibitor, DPP-4i) and empagliflozin (a sodium-glucose cotransporter 2 inhibitor, SGLT2i) on the differential expression of renal HIF-1alpha/2alpha. Tissue expression of prolylhydroxylase 3 (PHD3), a key regulator of HIF-2alpha stability, was also highlighted in a diabetic nephropathy rat model. Type 1 diabetes mellitus was induced and diabetic rats were treated with either Vildagliptin or Empagliflozin (10 mg/kg/d each) for 12 weeks. Improvements in the kidney functional and histopathological parameters were addressed and correlated to changes in the renal expression of HIF-1alpha/2alpha, and PHD3. Urinary KIM-1 concentration was tested as a correlate to HIF pathway changes. FINDINGS: Both vildagliptin- and empagliflozin-treated groups exhibited significant improvement in the functional, pathological, and ultra-structural renal changes induced by chronic diabetes. Compared to the untreated group, renal gene expression of HIF-1alpha was decreased while that of HIF-2alpha was increased in both treated groups, with significantly greater effects observed with SGLT2i. Renal PHD3 immune-reactivity was also decreased by both drugs, again with better efficacy for the SGLT2i. Importantly, improvements in the diabetic kidney biochemical and structural biomarkers were significantly correlated to PHD3 reductions and HIF-2alpha increments. CONCLUSIONS: Both DPP-4i and SGLT2i could delay the progression of DN through their differential modulating effects on the PHD3/ HIF-2alpha pathway with significantly better efficacy for SGLT2i.