HIF1α deletion facilitates adipose stem cells to repair renal fibrosis in diabetic mice.

Abstract

Adipose stem cell (ASC) transplantation is a promising therapeutic strategy for diabetic renal fibrosis. Hypoxia-inducible factor 1α (HIF1α) is a negative regulatory factor of mitochondrial function. In the current study, we aimed to explore if HIF1α deletion protects against hyperglycemia-induced ASC damage and enhances the therapeutic efficiency of ASCs in diabetic renal fibrosis. Our data indicated that HIF1α was upregulated in ASCs in response to high glucose stimulation. Higher HIF1α expression was associated with ASC apoptosis and proliferation arrest. Loss of HIF1α activated mitophagy protecting ASCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting HIF1α-deleted ASCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c, and inflammatory markers. In addition, the engraftment of HIF1α-modified ASCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that HIF1α-modified ASCs reduced renal fibrosis. Collectively, our results demonstrate that ASCs may be a promising therapeutic treatment for ameliorating diabetes and the development of renal fibrosis and that the loss of HIF1α in ASCs may further increase the efficiency of stem cell-based therapy. These findings provide a new understanding about the protective effects of HIF1α silencing on ASCs and offer a new strategy for promoting the therapeutic efficacy of ASCs in diabetic renal fibrosis.