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

Hong Ye, Xiaofang Wang, Megan M. Constans, Caroline R. Sussman, Fouad Chebib, Maria Irazabal Mira, William Francis Young, Peter C Harris, Lawrence S. Kirschner, Vicente Torres

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F677-F686
JournalAmerican Journal of Physiology - Renal Physiology
Volume313
Issue number3
DOIs
StatePublished - Sep 1 2017

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Keywords

  • Autosomal dominant polycystic kidney disease
  • CAMP
  • Cell signaling
  • Polycystic kidney disease
  • Protein kinase A

ASJC Scopus subject areas

  • Physiology
  • Urology

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