The regulatory 1α subunit of protein kinase A modulates renal cystogenesis

Am J Physiol Renal Physiol. 2017 Sep 1;313(3):F677-F686. doi: 10.1152/ajprenal.00119.2017. Epub 2017 Jun 14.


The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic (Pkd1RC) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD.

Keywords: autosomal dominant polycystic kidney disease; cAMP; cell signaling; polycystic kidney disease; protein kinase A.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Carney Complex / diagnostic imaging
  • Carney Complex / enzymology*
  • Carney Complex / genetics
  • Cell Proliferation
  • Child
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / deficiency
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism*
  • Cysts / diagnostic imaging
  • Cysts / enzymology*
  • Cysts / genetics
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Kidney / enzymology*
  • Kidney / pathology
  • Kidney / physiopathology
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Liver Diseases / diagnostic imaging
  • Liver Diseases / enzymology*
  • Liver Diseases / genetics
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • PAX2 Transcription Factor / metabolism
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant / enzymology*
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Polycystic Kidney, Autosomal Dominant / physiopathology
  • STAT3 Transcription Factor / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • TRPP Cation Channels / genetics
  • Wnt Signaling Pathway
  • Young Adult
  • Zinc Finger Protein Gli3
  • ras Proteins / metabolism
  • src-Family Kinases / metabolism


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Gli3 protein, mouse
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • PAX2 Transcription Factor
  • PRKAR1A protein, human
  • Pax2 protein, mouse
  • Prkar1a protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • TRPP Cation Channels
  • Zinc Finger Protein Gli3
  • polycystic kidney disease 1 protein
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins

Supplementary concepts

  • Polycystic liver disease