title: Kidney injury accelerates cystogenesis via pathways modulated by heme oxygenase and complement.
abstract: AKI accelerates cystogenesis. Because cystogenic mutations induce strong transcriptional responses similar to those seen after AKI, these responses may accelerate the progression of cystic renal disease. Here, we modulated the severity of the AKI-like response in Cys1(cpk/cpk) mice, a model that mimics autosomal recessive polycystic kidney disease. Specifically, we induced or inhibited activity of the renoprotective enzyme heme oxygenase (HO) and determined the effects on renal cystogenesis. We found that induction of HO attenuated both renal injury and the rate of cystogenesis, whereas inhibition of HO promoted cystogenesis. HO activity mediated the response of NFκB, which is a hallmark transcriptional feature common to both cystogenesis and AKI. Among the HO-modulated effects we measured, expression of complement component 3 (C3) strongly correlated with cystogenesis, a functionally relevant association as suggested by Cys1(cpk/cpk) mice with genetically induced C3 deficiency. Because both C3 deficiency and HO induction reduce cyst number and cyst areas, these two factors define an injury-stimulated cystogenic pathway that may provide therapeutic targets to slow the formation of new renal cysts and the growth of existing cysts.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, USA.
authors.forename: Juling
authors.initials: J
authors.lastname: Zhou
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Cui
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mrug
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Yoder
authors.forename: Martin R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.forename: Michal
authors.initials: M
authors.lastname: Mrug
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003176:Complement C3 / Q000502:physiology*; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000502:physiology; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000503:physiopathology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D003176:Complement C3; C449819:Cys1 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D006419:Heme Oxygenase (Decyclizing)