常染色体显性多囊肾病
多囊肾病
包装D1
生物
细胞生物学
医学
内科学
内分泌学
激酶
癌症研究
下调和上调
MAPK/ERK通路
蛋白激酶A
肾脏疾病
肾
作者
Xiaofang Wang,Li Jiang,Ka Thao,Caroline Sussman,Timothy LaBranche,Michael Palmer,Peter Harris,G. Stanley McKnight,Klaus Hoeflich,Stefanie Schalm,Vicente Torres
出处
期刊:Journal of the American Society of Nephrology
[American Society of Nephrology]
日期:2022-03-02
卷期号:: ASN.2021081125-ASN.2021081125
标识
DOI:10.1681/asn.2021081125
摘要
Background: Upregulation of cAMP-dependent and -independent PKA signaling is thought to promote cystogenesis in polycystic kidney disease (PKD). PKA-I regulatory subunit RIα is increased in kidneys of orthologous mouse models. Kidney-specific knockout of RIα upregulates PKA activity, induces cystic disease in wild-type mice, and aggravates it in Pkd1 RC/RC mice. Methods: PKA-I activation or inhibition was compared to EPAC activation or PKA-II inhibition using Pkd1 RC/RC metanephric organ cultures. The effect of constitutive PKA (preferentially PKA-I) downregulation in vivo was ascertained by kidney-specific expression of a dominant negative RIαB allele in Pkd1 RC/RC mice obtained by crossing Prkar1α R1αB/WT , Pkd1 RC/RC , and Pkhd1-Cre mice (C57BL/6 background). The effect of pharmacologic PKA inhibition using a novel, selective PRKACA inhibitor (BLU2864) was tested in mIMCD3 3D cultures, metanephric organ cultures, and Pkd1 RC/RC mice on a C57BL/6 x 129S6/Sv F1 background. Mice were sacrificed at 16 weeks of age. Results: PKA-I activation promoted and inhibition prevented ex vivo P-Ser133 CREB expression and cystogenesis. EPAC activation or PKA-II inhibition had no or only minor effects. BLU2864 inhibited in vitro mIMCD3 cystogenesis and ex vivo P-Ser133 CREB expression and cystogenesis. Genetic downregulation of PKA activity and BLU2864 directly and/or indirectly inhibited many pro-proliferative pathways and were both protective in vivo . BLU2864 had no detectable on- or off-target adverse effects. Conclusions: PKA-I is the main PKA isozyme promoting cystogenesis. Direct PKA inhibition may be an effective strategy to treat PKD and other conditions where PKA signaling is upregulated. By acting directly on PKA, the inhibition may be more effective than or substantially increase the efficacy of treatments that only affect PKA activity by lowering cAMP.
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