Mechanisms And Functions Of Nrf2-mediated Antioxidant Pathway In Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease?ADPKD?is one of the most common monogenic kidney disease.It is mainly characterized by cystic dilatation of the renal tubules,which destroys the kidney structure and leads to a decline in renal function,which ultimately leads to End-stage renal failure?ESRD?^[1,2].ADPKD is caused predominantly by mutations in two genes,PKD1 and PKD2,which encode polycystin 1?PC1?and polycystin 2?PC2?,respectively.Although the genetic basis of ADPKD has been established for over two decades,the molecular mechanisms responsible for the development of ADPKD remain poorly understood,and no curative treatment is currently available.In this study,we performed transcriptomic and proteomic analysis in an ADPKD mouse model?Pkd1 knockout mouse?.We found that the mRNA and protein expression of 287 genes were significantly down-regulated in the kidneys of ADPKD mice compared to wild type mice.Gene ontology?GO?analysis of these genes revealed that one-third of the gene products are localized in mitochondria,and more than two-thirds of the genes are associated with redox pathways.These results suggest that dysregulation of the mitochondrial function and redox signaling transduction pathway might be involved in ADPKD progression.Recent studies have shown that mitochondrial function abnormalities and increased oxidative stress index can be observed in the early stage of ADPKD patients^[6-8],suggesting that mitochondrial abnormalities may be associated with disease.Abnormal mitochondrial structure and function will lead to accumulation of reactive oxygen species?ROS?^[9].Consistent with this,we observed that ROS were significantly increased in kidney tissues and primary cystic epithelial cells derived from ADPKD mice.The intracellular ROS is determined by two factors:the production of ROS and ROS elimination mediated by antioxidant pathways.Transcription factor Nrf2?NF-E2-related factor 2?is one of the key regulators of antioxidant pathways.We found that Nrf2 and its downstream antioxidant-related target genes were significantly downregulated in ADPKD kidneys.To investigate the role of Nrf2-mediated antioxidant pathways in the development of ADPKD,we crossed Pkd1 knockout mice with Nrf2 knockout mice.In vivo functional studies have shown that loss of Nrf2 leads to accelerated ADPKD progression.Cruciferous vegetables are rich in natural compound SFN?Sulforaphan?.SFN can inhibit the interaction between KEAP1 and Nrf2,resulting in the accumulation of Nrf2 into the nucleus,thereby activates the expression of downstream antioxidant genes^[10].Administration of SFN in ADPKD mice significantly attenuated cyst formation and improved renal function.These studies may help us understand the mechanisms and function of Nrf2-mediated antioxidant pathway in ADPKD and allow us to design more effective therapeutic strategies for ADPKD treatment.