2022•Journal of the American Society of NephrologyRequires access
Comparative Transcriptomics of PKD1 Downregulation and PKA Upregulation or Downregulation
Xiaoyan Li, Xiaofang Wang, Jiang Li, Peter C. Harris, Xiaogang Li, Vicente E. Torres
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Abstract
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