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.
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.