Targeting Cyclic AMP and Protein Kinase A Signaling to Treat ADPKD: An Efficacious Strategy with Further Potential
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited renal cystic disease with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is responsible for 5%-10% of kidney failure world-wide. Over the last two decades there has been substantial progress in understanding the disease, but only 1 drug, tolvaptan, has been approved by regulatory agencies to treat ADPKD, and is currently used in clinical practice. The effect of tolvaptan on disease progression is modest and its administration requires a burdensome Risk Evaluation and Mitigation Strategy (REMS) because of potential hepatotoxicity. Therefore, treatments that enhance its efficacy and safety or are better than tolvaptan are needed. The path for tolvaptan to become the first approved treatment for ADPKD relied on overwhelming evidence for the important role of vasopressin, G?s protein, cyclic AMP, and protein kinase A (PKA) signaling in this disease. Since the full therapeutic potential of tolvaptan cannot be reached because its administration is accompanied and limited by polyuria, additional treatments targeting the same pathway at different levels are attractive. We have found that constitutive kidney specific activation of PKA markedly aggravates ADPKD in polycystic mice and by itself induces kidney cystic disease in mice genetically normal. RNA sequencing analysis of kidneys from these mice showed a high degree of overlap between genes differentially expressed as result of a Pkd1 mutation or as result of constitutive PKA activation, further supporting the importance of PKA in ADPKD. This transcriptomic analysis and additional preliminary observations identified several potential therapeutic targets. The work proposed in this application focuses on some of these targets, DNA methylation and epigenetic regulators in Project2; NOX4 and mitochondrial metabolism in Project 3; and vasopressin V1a and V1b receptors, neuropeptide (NPY), and ?-arrestin signaling in Project 4. None of these has been previously evaluated in ADPKD. In addition, Project 1 seeks to identify novel germline or somatic genetic variants in the G?s-PKA pathway associated with disease severity or progression and to reveal new therapeutic targets. Project 4 will also explore the potential additive or synergistic value of treatments expected or found to be individually effective in the four projects of this focused program. We anticipate that the proposed studies will substantially expand the understanding of the pathogenesis of ADPKD, confirm the critical role of the G?s-PKA and associated pathways, and open the door to new therapies that will enhance the efficacy of or will be more effective than tolvaptan. Since ADPKD can be considered an example G?s-PKA signalopathy, a family of diseases ranging from endocrine and metabolic diseases to cancer, the knowledge generated by this Program may not only impact ADPKD but also many other diseases. Project 1. Are DNA variants in cAMP signaling pathway genes implicated in the causation and/or modification of the ADPKD spectrum phenotype? Overwhelming evidence links cAMP/PKA and related signaling pathways to pathogenesis in autosomal dominant polycystic kidney disease (ADPKD). However, there are question of which specific parts of the pathway may be involved in ADPKD development. Here we take an unbiased approach to answer this question by genetic screening of ADPKD patients for variants in 165 cAMP/PKA and related signaling pathway genes. From this analysis we will determine if pathogenic variants in one or more of these genes can cause ADPKD or be a significant modifier of disease severity. In addition, common variants found in cAMP/PKA and related signaling pathway genes will be tested in a cohort of >5000 ADPKD patients to see if they have subtle effects on how ADPKD presents and progresses. Finally, we will test if somatic pathogenic variants develop in cyst lining cells in ADPKD kidneys th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310488
Entities
People
- Vicente Torres
Organizations
- Mayo Clinic
- United States Army