Comparative Transcriptomics of PKD1 Downregulation and PKA Upregulation or Downregulation

Background: Constitutive activation of PKA by a kidney specific knock-out of Prkar1α, encoding the regulatory 1α subunit, induces a cystic phenotype in wild-type mice and aggravates polycystic kidney disease (PKD) in Pkd1RC/RC mice (AJP Renal Physiol 313:F677, 2017) whereas constitutive inhibition of PKA by kidney specific expression of R1α subunits unable to release catalytic subunits in the presence of cAMP ameliorates PKD in the same model (JASN PMID: 35236775, 2022). Methods: RNA sequencing of wild-type, constitutively activated PKA (CA-PKA) wild-type, Pkd1RC/RC, CA-PKA Pkd1RC/RC, and constitutively inhibited PKA (CI-PKA) Pkd1RC/RC kidneys was performed to compare the effects of PKA activation and Pkd1 downregulation on gene expression. Differential gene expressions and pathways were identified using DESeq2 and GOstats package, respectively. Results: 15,983 transcripts with more than 10 reads were identified. Thirty-six percent (5,710) and 22% (3,574) were differentially expressed (adjusted P<0.05) in CA-PKA and Pkd1RC/RC kidneys respectively compared to wild-type kidneys; 2,674 (47%) differentially expressed transcripts (DETs) in CA-PKA were also differentially expressed in Pkd1RC/RC kidneys; log2 fold DET changes were highly and positively correlated (Figure 1). Fifty-six percent (9,005) and 19% (3,063) transcripts were differentially expressed in CA-PKA Pkd1RC/RC and CI-PKA PKA Pkd1RC/RC kidneys respectively compared to Pkd1RC/RC controls; 2,252 (25%) DETs in CA-PKA Pkd1RC/RC were also differentially expressed in CI-PKA PKA Pkd1RC/RC kidneys; log2 fold DET changes were inversely correlated (Figure 2). DETs in CA-PKA wild-type, Pkd1RC/RC, CA-PKA Pkd1RC/RC, and CI-PKA Pkd1RC/RC kidneys compared to their controls included 46, 26, 66 and 25% respectively of 351 PKA-dependent out of 10,190 analyzed transcripts in mouse cortical collecting duct cells (PNAS 114:E8875, 2017)Figure 1Figure 2Conclusions: This comparative transcriptomic analysis supports the importance of cAMP and PKA signaling in the pathogenesis of PKD and identifies additional therapeutic targets. Funding: NIDDK Support