Indoxyl Sulfate-upregulated ApoJ Expression Aggravated Chronic Kidney Disease Via Mitophagy Inhibition

Chronic kidney disease(CKD)has affected more than 10% of the population in the world.Renal fibrosis is the main pathological process of end-stage CKD.Excessive accumulation and deposition of extracellular matrix while leads to gradual loss renal function are the main causes of renal fibrosis.The epithelial to mesenchymal transition(EMT)signaling pathway is one of the main sources of extracellular matrix.Accumulation of indoxyl sulfate(IS)was appeared in patients with CKD.IS,a small molecule nephrotoxin,causes inflammation and oxidative stress,promotes glomerular sclerosis and interstitial fibrosis,and accelerates the decline of renal function.Therefore,IS played an important role in renal dysfunction and disorders.Both hemodialysis and drμg therapy exerts low efficiency in reduction of serum IS level in clinical patients.Identification of therapeutic targets that relief the effects of IS may block the progression of CKD.Previously,studies have shown that ApoJ,as a stress-induced protein,was significantly increased in patients with CKD and renal disease models.In the present study,the correlation between the level of serum IS,renal function and serum ApoJ level was analyzed in clinical samples.The results showed that IS was negatively correlated with renal function,but positively correlated with the level of ApoJ.The association between ApoJ and renal damage was also observed in UUO mice model.In order to explore the role of ApoJ in IS-induced pathogenesis.The IS-treated renal epithelial cell was subjected iTRAQ quantitative proteomics analysis.The results showed that IS activated EMT signaling pathway and increased ROS production in control cell,but not in ApoJ knockdown cell.Furthermore,knockdown of ApoJ reversed IS-inhibited mitophagy.This study aimed to explore the role of ApoJ in CKD and provide a new endogenous target for slowing down or treating CKD.Thus,the result sμggested that IS impaired mitophagy,induced intracellular ROS accumulation and lead EMT.Knockdown of ApoJ prevented IS-associated pathogenesis by restoration of mitophagy which removed damaged mitochondria,reduced intracellular ROS level,therefore,inhibited EMT progression.