Tubular MYDGF slows the progression of chronic kidney disease by maintaining mitochondrial homeostasis
Mitochondrial dysfunction is a key event in driving maladaptive repair of tubular epithelial cells during the transition from acute kidney injury to chronic kidney disease (CKD). Therefore, identifying the potential targets involved in mitochondrial dysfunction in tubular epithelial cells has clinical importance. Although our previous studies demonstrated that myeloid-derived growth factor (MYDGF) derived from podocyte attenuated glomerular injury by inhibiting mitotic catastrophe of podocyte, the function of MYDGF in tubular epithelial cells still keeps unknown. In this study, we found that MYDGF expression was significantly decreased in the cortex of kidney, especially in proximal tubules, from mice with CKD. Notably, the downregulation of MYDGF was further confirmed in renal tubules from CKD subjects. Tubule-specific deletion of MYDGF exacerbated kidney injury in mice with CKD. However, overexpression of MYDGF attenuated kidney fibrosis by remodeling mitochondrial homeostasis in tubular epithelial cells. Mechanistically, renal tubule MYDGF positively regulated the expression of isocitrate dehydrogenase 2 (IDH2), then restoring mitochondrial homeostasis and slowed the progression of CKD. Thus, our studies indicate that MYDGF derived from tubules may be an effective innovative therapeutic strategy for patients with CKD. Overall design: The gene expression of 3 samples from the HK-2 cells with aristolochic acid treatment was compared to 3 NC samples by RNA sequencing. The gene expression of 3 samples from the HK-2 cells with aristolochic acid treatment was compared to 3  samples from the HK-2 cells with overexpression of MYDGF and aristolochic acid treatment by RNA sequencing.