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Kidney Week

Abstract: PO1206

Protein Kinase A Downregulation Delays the Development and Progression of Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Wang, Xiaofang, Mayo Clinic, Rochester, Minnesota, United States
  • Jiang, Li, Mayo Clinic, Rochester, Minnesota, United States
  • Thao, Ka, Mayo Clinic, Rochester, Minnesota, United States
  • Sussman, Caroline R., Mayo Clinic, Rochester, Minnesota, United States
  • Labranche, Timothy Paul, Blueprint Medicines, Waban, Massachusetts, United States
  • Palmer, Michael R., Blueprint Medicines, Waban, Massachusetts, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Mcknight, Stanley, University of Washington, Seattle, Washington, United States
  • Hoeflich, Klaus P., Blueprint Medicines, Waban, Massachusetts, United States
  • Schalm, Stefanie S., Blueprint Medicines, Waban, Massachusetts, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
Background

Upregulation of cAMP-dependent as well as -independent PKA signaling is thought to promote cystogenesis in polycystic kidney disease (PKD). We have shown that the PKA-I regulatory subunit RIα is increased in kidneys of orthologous mouse models and that kidney specific knockout of RIα upregulates PKA activity, induces cystic disease in wild-type mice, and aggravates it in Pkd1RC/RC mice.

Methods

This study was designed to ascertain (1) the effect of PKA-I activation or inhibition compared to EPAC or PKA-II inhibition on ex vivo cystogenesis using Pkd1RC/RC metanephric organ cultures, (2) whether PKA (preferentially PKA-I) downregulation by kidney specific expression of a dominant negative RIαB allele (obtained by crossing Prkar1αR1αB/WT, Pkd1RC/RC, and Pkhd1-Cre mice) is protective in vivo in Pkd1RC/RC mice on the C57BL/6 background, (3) whether a novel, small molecule, selective PRKACA inhibitor (BLU0588) blocks in vitro mIMCD3 and ex vivo cystogenesis (40-200 nM) and is protective in vivo in Pkd1RC/RC mice on the C57BL/6 x 129S6/Sv F1 background (30 mg/kg b.w. by oral gavage starting at 4 weeks of age). Mice were sacrificed at 16 weeks of age.

Results

PKA-I activation promoted, and inhibition prevented, ex vivo cystogenesis, whereas EPAC activation or PKA-II activation or inhibition had no or only minor effects. BLU0588 inhibited in vitro mIMCD3 cystogenesis and ex vivo cystogenesis. Genetic and pharmacological downregulation of PKA activity were both protective in vivo (Table). BLU0588 had no detectable on- or off-target adverse effects.

Conclusion

PKA-I is the main effector of cAMP in cystogenesis. Direct downregulation of PKA activity is demonstrated as a novel strategy to treat PKD. By acting directly on PKA, PKA inhibitors may be more effective alone or substantially augment the efficacy of treatments that only affect the cAMP-dependent PKA activity by lowering cAMP.

Group (sex)Body Wt (g)Kidney/Body Wt x 100 (g)Cyst index
(%)
P. creatinine
(mg/dl)
PKA activity
(pmol ATP/min/mg protein)
 BasalTotal
Control
(F=28, M=43)
26.2±4.12.06±0.4513.7±6.70.32±0.10459±1762868±741
RIαB-ON
(F=9, M=15)
26.8±4.51.63±0.409.25±3.520.24±0.09427±1761877±517
P-value0.61<0.001<0.0010.0010.44<0.001
Control
(F=10, M=9)
25.5±3.13.13±0.6028.6±5.70.39±0.04455±922387±603
BLU0588
(F=9,M=9)
25.3±2.42.61±0.5222.4±6.40.38±0.06141±34379±138
P-value0.860.0080.0030.55<0.001<0.001