Tsc2 mutation induces renal tubular cell nonautonomous disease  

作　　者：Prashant Kumar Fahad Zadjali Ying Yao Daniel Johnson Brian Siroky Aristotelis Astrinidis Peter Vogel Kenneth W.Gross John J.Bissler 

机构地区：[1]Department of Pediatrics,University of Tennessee Health Science Center and Le Bonheur Children's Hospital,Memphis,TN 38103,USA [2]Children's Foundation Research Institute(CFRI),Le Bonheur Children's Hospital,Memphis,TN 38105,USA [3]Department of Clinical Biochemistry,College of Medicine&Health Sciences,Sultan Qaboos University,Muscat 123,Oman [4]Molecular Bioinformatics Center,University of Tennessee Health Science Center,Memphis,TN 38163,USA [5]Department of Veterinary Pathology,St.Jude Children's Research Hospital,Memphis,TN 38105,USA [6]Department of Molecular and Cellular Biology,Roswell Park Comprehensive Cancer Center,Buffalo,NY 14263,USA [7]Pediatric Medicine Department,St.Jude Children's Research Hospital,Memphis,TN 38105,USA

出　　处：《Genes & Diseases》2022年第1期187-200,共14页基因与疾病（英文）

基　　金：This work was supported by DoD(No.W81XWH-14-1-0343)(JJB);Federal Express Chair of Excellence(JJB),and Children’s Foundation Research Institute(JJB).

摘　　要：TSC renal cystic disease is poorly understood and has no approved treatment.In a new principal cell-targeted murine model of Tsc cystic disease,the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing,although these cells exhibit a Tsc-mutant disease phenotype.We used a newly derived targeted murine model in lineage tracing and extracellular vesicle(EV)characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis.Using lineage tracing experiments,we found principal cells undergo clonal expansion but contribute very few cells to the cyst.We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys,excrete fewer EVs in urine,and contain EVs in cyst fluid.Moreover,the loss of Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium,such that the epithelium develops increased secretory and proliferative pathway activity.We demonstate that the mTORC1 pathway activity is independent form the EV production,and that the EV effects for a single cell line can vary significantly.TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.

关 键 词：Cell nonautonomous trait Polycystic kidney disease Renalcystogenesis Tuberous sclerosis complex 

分 类 号：R692[医药卫生—泌尿科学]