Affiliation:
1. Department of Nephrology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 China
2. Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 China
3. Tongji School of Pharmacy, Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 China
4. The Key Laboratory of Infection and Immunity of Shandong Province Department of Pharmacology School of Basic Medical Sciences Shandong University Jinan 250100 China
Abstract
AbstractNuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR‐γ dependent way. Podocyte‐specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.
Funder
National Natural Science Foundation of China