Abstract
Autosomal dominant (AD) polycystic kidney disease (PKD) is a major cause of end-stage renal disease, with neither a cure, nor an approved treatment to slow its progression. In the past decade significant advances have been made in understanding the cellular signaling pathways disrupted in PKD. Understanding the changes in signaling pathways linked to mutations in PKD1 and PKD2 as well as other renal cystic genes led to preclinical trials and Phase II & III human trials to ameliorate PKD progression. Since PKD is a proliferative disease, some treatments are aimed at neoplastic cell proliferation (i.e. src and MAPK inhibition). PKD is also associated with decreased cellular calcium and increased cAMP, so other treatments targeted cellular Ca (i.e. calcimimetics and polycystin 2 agonists) or G-protein linked receptors (i.e. the vasopressin V2 receptor and somatostatin receptor inhibitors). Fluid secretion through the cystic fibrosis transmembrane conductance regulator (CFTR, a chloride channel) also contributes to disease progression and therapies blocking chloride secretion are also possible therapeutic agents. Significantly, the renin- angiotensin system is responsible, at least in part, for PKD associated hypertension, and drugs targeting this pathway are also being evaluated as therapies for ADPKD progression. Assessment of efficacy in humans with ADPKD is complicated by the slow progressive nature of the disease, but the CRISP imaging studies have provided important data on renal cystic enlargement over time. Based on numerous preclinical studies in rodent models, several human clinical trials are currently being performed, suggesting that a treatment to inhibit progression of ADPKD and other renal cystic conditions may be available in the near future.
Highlights
Vasopressin V2R antagonists and the SSTR agonists both are in clinical trials that are providing evidence of efficacy and are likely to be the first possible therapeutic agents to be used in ADPKD patients
As there are no vasopressin 2 receptors in liver and there is limited data on efficacy of SSTR in the kidney, there may need to be combination treatments to achieve efficacy in both principal organs affected in HRFC diseases like ADPKD
The most recent, disappointing, clinical studies with mTOR inhibitors suggest that pathway may not be enthusiastically supported for further clinical trials
Summary
Autosomal dominant (AD) polycystic kidney disease (PKD) is a major cause of end-stage renal disease, with neither a cure, nor an approved treatment to slow its progression. Hallmarks of renal cystic diseases include: a) increased cell proliferation, b) increased apoptosis, c) increased fluid secretion into the cystic space, d) increased connective tissue expression and fibrosis, e) altered state of differentiation, f) inappropriate localization of membrane-bound proteins (transporters and channels), g) altered cellular responses to certain stimuli (i.e. cAMP), and h) altered expression of a diverse group of mRNAs and proteins. This knowledge, albeit incomplete, has provided sufficient data to begin to develop treatments for these renal cystic conditions. We will outline the general signaling pathways targeted in HRFC diseases, discuss results from animal studies and the status of human trials
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