title: Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease.
abstract: cAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center and Salt Lake City Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Sara
authors.initials: S
authors.lastname: Rees
authors.forename: Wararat
authors.initials: W
authors.lastname: Kittikulsuth
authors.forename: Karl
authors.initials: K
authors.lastname: Roos
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strait
authors.forename: Alfred
authors.initials: A
authors.lastname: Van Hoek
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics; D000242:Cyclic AMP / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D019426:Integrases / Q000235:genetics; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control; D007685:Kidney Tubules, Collecting / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics; D019076:Transgenes
chemical_list: D000262:Adenylyl Cyclases; D051399:Aquaporin 2; D000242:Cyclic AMP; D019426:Integrases; D050396:TRPP Cation Channels; C496024:Aqp2 protein, mouse; C045073:Cre recombinase; C121100:adenylyl cyclase 6