Objectives: In diabetic nephropathy (DN), hypoxia-inducible factor-1α (HIF-1α) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF-1α, such as haem oxygenase-1 (HO-1), but the exact mechanisms are incompletely understood.
Materials and methods: Mice with proximal tubule-specific knockout of HIF-1α (PT-HIF-1α-/- mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl2 ) was applied to HK-2 cells.
Results: Our study first verified that conditional knockout of HIF-1α worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT-HIF-1α-/- mice. In vitro study showed that compared to control group, HK-2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF-1α or treatment with a HO-1 agonist. Importantly, cotreatment with a HIF-1α inhibitor and a HO-1 agonist rescued the HK-2 cells from the negative impacts of the HIF-1α inhibitor.
Conclusions: These data revealed that HIF-1α exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO-1 upregulation.
© 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.