Sav1Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis.
Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation ofSav1in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss ofSav1induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development fromSav1loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA janet_leung@med.unc.edu wykim@med.unc.edu.|Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Janet Y
JY
Leung
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Harper L
HL
Wilson
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kristin J
KJ
Voltzke
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lindsay A
LA
Williams
Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
Hyo Jin
HJ
Lee
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Sara E
SE
Wobker
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA janet_leung@med.unc.edu wykim@med.unc.edu.|Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
William Y
WY
Kim
D058186:Acute Kidney Injury / Q000235:genetics / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D034341:Aristolochic Acids; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D011166:Porphyrins; D050796:STAT3 Transcription Factor; C485935:Sav1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000077362:Verteporfin; D003094:Collagen; C000228:aristolochic acid I
fibrosis; mouse; renal; senescence