DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

• Published in: Journal of cellular physiology 2019-03, Vol.234 (3), p.3043-3057
• Main Authors: Sheng, Junqin, Li, Hongyan, Dai, Qin, Lu, Chang, Xu, Min, Zhang, Jisheng, Feng, Jianxun
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Cytoplasm; Diabetes; Diabetes mellitus; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic nephropathy; diabetic renal damage; Dual Specificity Phosphatase 1 - genetics; DUSP1; Fibrosis; Fission; Gene Expression Regulation - genetics; Glucose metabolism; Homeostasis; Humans; Hyperglycemia; Hypertrophy; Kidney - metabolism; Kidney - pathology; MAP Kinase Kinase 4 - genetics; MAP Kinase Signaling System - genetics; Membrane Proteins - genetics; Metabolism; Mff; Mice; Mitochondria; Mitochondria - genetics; Mitochondrial Dynamics - genetics; mitochondrial fission; Mitochondrial permeability transition pore; Mitochondrial Proteins - genetics; Mitophagy - genetics; Nephropathy; Oxidative stress; Pathogenesis; Phosphorylation; Protein phosphatase; Proteins; Renal function; Signal transduction; Signal Transduction - genetics; Therapeutic applications
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27124

Excessive mitochondrial fission has been identified as the pathogenesis of diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation in the setting of DN remains unknown. In the current study, we found that dual‐specificity protein phosphatase‐1 (DUSP1) was actually downregulated by chronic hyperglycemia stimulus. Lower DUSP1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, defective DUSP1 expression activated JNK pathway, and the latter selectively opened mitochondrial fission by modulating mitochondrial fission factor (Mff) phosphorylation. Excessive Mff‐related mitochondrial fission evoked mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria‐dependent cellular apoptosis in the setting of diabetes. However, overexpression of DUSP1 interrupted Mff‐related mitochondrial fission, reducing hyperglycemia‐mediated mitochondrial damage and thus improving renal function. Overall, we have shown that DUSP1 functions as a novel malefactor in diabetic renal damage that mediates via modifying Mff‐related mitochondrial fission. Thus, finding strategies to regulate the balance of the DUSP1‐JNK‐Mff signaling pathway and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice. In summary, our report highlights novel signal pathways controlling the progression of diabetic nephropathy via modulation of mitochondrial homeostasis: downregulated DUSP1 induced by hyperglycemia activates JNK pathway, opening Mff‐mediated mitochondrial fission. The imbalance in mitochondrial dynamics augments glomerular apoptosis and impairs renal function. In light of these findings, strategies to regulate the balance of the DUSP1‐JNK‐Mff signaling pathways and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice.