HIF-1α ameliorates tubular injury in diabetic nephropathy via HO-1-mediated control of mitochondrial dynamics

Objectives In diabetic nephropathy (DN), hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF-1 alpha, 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-1 alpha (PT-HIF-1 alpha(-/-)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-1 alpha worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT-HIF-1 alpha(-/-)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-1 alpha or treatment with a HO-1 agonist. Importantly, cotreatment with a HIF-1 alpha inhibitor and a HO-1 agonist rescued the HK-2 cells from the negative impacts of the HIF-1 alpha inhibitor. Conclusions These data revealed that HIF-1 alpha exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO-1 upregulation.