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Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE128524 | GEO | 2019/06/20

REPOSITORIES: GEO

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Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease.

Project description:Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.

| S-EPMC6551191 | biostudies-literature

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (RNA-Seq)

Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.

2019-06-20 | GSE128522 | GEO

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (ChIP-Seq)

2019-06-20 | GSE128521 | GEO

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease

Project description:Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease

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Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (RNA-Seq)

Project description:Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (RNA-Seq)

| PRJNA528012 | ENA

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (ChIP-Seq)

Project description:Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (ChIP-Seq)

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Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.

Project description:Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3',5'-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.

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Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease.

Project description:Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.

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Autosomal dominant polycystic kidney disease and transplantation.

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder affecting 1 in 1,000 people and responsible for 10% of cases of the end stage renal disease (ESRD). Apart from renal manifestations, changes in other organs may be present. In the absence of contraindications, patients with ADPKD and ESRD should be referred to renal transplantation. The ADPKD patient may also need liver transplantation, or combined liver and kidney transplantation. Also, the patient with ADPKD may become a potential organ donor. The aim of our paper is to review the problems that the physicians deal with in ADPKD patients in pre- and post-transplant period.

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Autosomal dominant polycystic kidney disease: updated perspectives.

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, characterized by renal and extra-renal fluid-filled cyst formation and increased kidney volume that eventually leads to end-stage renal disease. ADPKD is considered the fourth leading cause of end-stage renal disease in the United States and globally. Care of patients with ADPKD was, for a long time, limited to supportive lifestyle measures, due to the lack of therapeutic strategies targeting the main pathways involved in the pathophysiology of ADPKD. As the first FDA approved treatment of ADPKD, Vasopressin (V2) receptor blocking agent, tolvaptan, is an urgently awaited advance for ADPKD patients. In our review, we also shed some lights on what is beyond Tolvaptan as there are other medications in the pipeline and many medications have been or are currently being studied in clinical trials such as Tesevatinib, Metformin and Pravastatin, with the goal of slowing the rate of progression of ADPKD by reducing the increase in total kidney volume or maintaining eGFR. Here, we review updates in the perspectives and management of ADPKD.

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