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"ADPKD-omics": determinants of cyclic AMP levels in renal epithelial cells.

ABSTRACT: The regulation of cyclic adenosine monophosphate (cAMP) levels in kidney epithelial cells is important in at least 2 groups of disorders, namely water balance disorders and autosomal dominant polycystic kidney disease. Focusing on the latter, we review genes that code for proteins that are determinants of cAMP levels in cells. We identify which of these determinants are expressed in the 14 kidney tubule segments using recently published RNA-sequencing and protein mass spectrometry data ("autosomal dominant polycystic kidney disease-omics"). This includes G protein-coupled receptors, adenylyl cyclases, cyclic nucleotide phosphodiesterases, cAMP transporters, cAMP-binding proteins, regulator of G protein-signaling proteins, G protein-coupled receptor kinases, arrestins, calcium transporters, and calcium-binding proteins. In addition, compartmentalized cAMP signaling in the primary cilium is discussed, and a specialized database of the proteome of the primary cilium of cultured "IMCD3" cells is provided as an online resource (https://esbl.nhlbi.nih.gov/Databases/CiliumProteome/). Overall, this article provides a general resource in the form of a curated list of proteins likely to play roles in determination of cAMP levels in kidney epithelial cells and, therefore, likely to be determinants of progression of autosomal dominant polycystic kidney disease.

SUBMITTER: Mehta YR

PROVIDER: S-EPMC10671900 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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"ADPKD-omics": determinants of cyclic AMP levels in renal epithelial cells.

Mehta Yash R YR Lewis Spencer A SA Leo Kirby T KT Chen Lihe L Park Euijung E Raghuram Viswanathan V Chou Chung-Lin CL Yang Chin-Rang CR Kikuchi Hiroaki H Khundmiri Syed S Poll Brian G BG Knepper Mark A MA

Kidney international 20211029 1

The regulation of cyclic adenosine monophosphate (cAMP) levels in kidney epithelial cells is important in at least 2 groups of disorders, namely water balance disorders and autosomal dominant polycystic kidney disease. Focusing on the latter, we review genes that code for proteins that are determinants of cAMP levels in cells. We identify which of these determinants are expressed in the 14 kidney tubule segments using recently published RNA-sequencing and protein mass spectrometry data ("autosom ...[more]

PMID: 34757121

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Project description:Autocrine/paracrine factors generated in response to 17β-estradiol (E2) within the fallopian tube (FT) facilitate fertilization and early embryo development for implantation. Since cyclic AMP (cAMP) plays a key role in reproduction, regulation of its synthesis by E2 may be of biological/pathophysiological relevance. Herein, we investigated whether cAMP production in FT cells (FTCs) is regulated by E2 and environmental estrogens (EE's; xenoestrogens and phytoestrogens). Under basal conditions, low levels of extracellular cAMP were detectable in bovine FTCs (epithelial cells and fibroblasts; 1:1 ratio). Treatment of FTCs with forskolin (AC; adenylyl cyclase activator), isoproterenol (β-adrenoceptor agonist) and IBMX (phosphodiesterase (PDE) inhibitor) dramatically (>10 fold) increased cAMP; whereas LRE1 (sAC; soluble AC inhibitor) and 2',5'-dideoxyadenosine (DDA; transmembrane AC (tmAC)) inhibitor decreased cAMP. Comparable changes in basal and stimulated intracellular cAMP were also observed. Ro-20-1724 (PDE-IV inhibitor), but not milrinone (PDE-III inhibitor) nor mmIBMX (PDE-I inhibitor), augmented forskolin-stimulated cAMP levels, suggesting that PDE-IV dominates in FTCs. E2 increased cAMP levels and CREB phosphorylation in FTCs, and these effects were mimicked by EE's (genistein, 4-hydroxy-2',4',6'-trichlorobiphenyl, 4-hydroxy-2',4',6'-dichlorobiphenyl). Moreover, the effects of E2 and EE were blocked by the tmAC inhibitor DDA, but not by the ERα/β antagonist ICI182780. Moreover, BAPTA-AM (intracellular-Ca2+ chelator) abrogated the effects of E2, but not genistein, on cAMP suggesting differential involvement of Ca2+. Treatment with non-permeable E2-BSA induced cAMP levels and CREB-phosphorylation; moreover, the stimulatory effects of E2 and EEs on cAMP were blocked by G15, a G protein-coupled estrogen receptor (GPER) antagonist. E2 and IBMX induced cAMP formation was inhibited by LRE1 and DDA suggesting involvement of both tmAC and sAC. Our results provide the first evidence that in FTCs, E2 and EE's stimulate cAMP synthesis via GPER. Exposure of the FT to EE's and PDE inhibitors may result in abnormal non-cyclic induction of cAMP levels which may induce deleterious effects on reproduction.

Dataset Information

"ADPKD-omics": determinants of cyclic AMP levels in renal epithelial cells.

Publications

"ADPKD-omics": determinants of cyclic AMP levels in renal epithelial cells.

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