AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice.

Abstract

Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

• Authors: Ya-Chun Han, Shi-Qi Tang, Yu-Ting Liu, Ai-Mei Li, Ming Zhan, Ming Yang, Na Song, Wei Zhang, Xue-Qin Wu, Can-Hui Peng, Hao Zhang, Shikun Yang
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 10 Pg. 925 (10 09 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34628484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Blood Glucose
• Collagen Type I
• Fibronectins
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species
• Streptozocin
• 8-Hydroxy-2'-Deoxyguanosine
• Metformin
• Creatinine
• Ubiquitin-Protein Ligases
• parkin protein
• Protein Kinases
• PTEN-induced putative kinase
• AMP-Activated Protein Kinases

Topics

• 8-Hydroxy-2'-Deoxyguanosine (metabolism)
• AMP-Activated Protein Kinases (metabolism)
• Animals
• Blood Glucose (metabolism)
• Blood Urea Nitrogen
• Cell Line
• Collagen Type I (metabolism)
• Creatinine (blood)
• Diabetes Mellitus, Experimental (blood, pathology)
• Diet, High-Fat
• Fibronectins (metabolism)
• Fibrosis
• Humans
• Interleukin-1beta (metabolism)
• Kidney (pathology, ultrastructure)
• Metformin (pharmacology)
• Mice, Inbred C57BL
• Mitochondria (metabolism, ultrastructure)
• Mitophagy (drug effects)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Protein Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Streptozocin
• Ubiquitin-Protein Ligases (metabolism)