title: Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts.
abstract: Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-α and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-α accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac-mimetic selectively induces TNF-α-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-α augmented the formation and activation of the RIPK1-dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-α in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD.
authors.affiliation: Department of Internal Medicine and.
authors.forename: Lucy X
authors.initials: LX
authors.lastname: Fan
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.forename: William E
authors.initials: WE
authors.lastname: Sweeney
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.forename: Ellis D
authors.initials: ED
authors.lastname: Avner
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D011247:Pregnancy; D050396:TRPP Cation Channels / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D004151:Dipeptides; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D050396:TRPP Cation Channels; D014409:Tumor Necrosis Factor-alpha; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; C585956:GT13072