CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation  

作　　者：Yan Zhang Emily A.Daniel July Metcalf Yuqiao Dai Gail A.Reif Darren P.Wallace 

机构地区：[1]Department of Internal Medicine,University of Kansas Medical Center,Kansas City,KS 66160-3018,USA [2]Jared Grantham Kidney Institute,University of Kansas Medical Center,Kansas City,KS 66160-3018,USA [3]Department of Molecular and Integrative Physiology,University of Kansas Medical Center,Kansas City,KS 66160-3018,USA

出　　处：《Journal of Molecular Cell Biology》2022年第7期49-61,共13页分子细胞生物学报（英文版）

基　　金：National Institute of Diabetes and Digestive and Kidney Disease(R01DK081579 to D.P.W.);fellowship grants from the PKD Foundation(to Y.Z.);Kansas Idea Network of Biomedical Research Excellence(K-INBRE,P20 GM103418 to Y.Z.).

摘　　要：Autosomal dominant polycystic kidney disease(ADPKD)is characterized by progressive enlargement of fluid-filled cysts,causing nephron loss and a decline in renal function.Mammalian target of rapamycin(mTOR)is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement;however,the mechanism for mTOR stimulation remains unclear.We discovered that calcium/calmodulin(CaM)dependent kinase IV(CaMK4),a multifunctional kinase,is overexpressed in the kidneys of ADPKD patients and PKD mouse models.In human ADPKD cells,CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase(S6K),a downstream target of mTOR.Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD cells.Moreover,inhibition of calcium/CaM-dependent protein kinase kinase-βand CaM,two key upstream regulators of CaMK4,also decreased mTOR signaling.The effects of KN-93 were independent of the liver kinase B1-adenosine monophosphate-activated protein kinase(AMPK)pathway,and the combination of KN-93 and metformin,an AMPK activator,had additive inhibitory effects on mTOR signaling and in vitro cyst growth.Our data suggest that increased CaMK4 expression and activity contribute to mTOR signaling and the proliferation of cystic cells of ADPKD kidneys.

关 键 词：ADPKD CaMK4 CaMKKβ CALMODULIN LKB1 AMPK 

分 类 号：R692[医药卫生—泌尿科学]