Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin‐1 and polycystin‐2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in‐depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…Tissue-, brain region-, and subcellular domain-specific decreases in PDE expression/activity and/or increases in cyclic nucleotide signaling have been implicated in select disease states, including some age-related deficits (193)(194)(195), Huntington's disease (196), social isolation (197), migrane (198)(199)(200)(201)(202), retinitis pigmentosa (203), infertility (112), prostate cancer (204), melanoma and basal cell carcinoma (175), cardiac hypertrophy (35,205), acrodysostosis (36), and polycystic kidney disease (206). Indeed, Mironid have developed PDE4 longform specific activators (mechanism as yet unknown; Table 4) for the treatment of polycystic kidney disease where increased adenylate cyclase activity caused by overexpression of vasopressin V2R receptors results in elevated cAMP levels that drive cyst growth and disease progression (207). There are several natural mechanisms by which PDE activity can be activated ( Figure 3), and it is our contention that these avenues could be manipulated phamacologically to trigger PDE activation.…”

Ciliary Genes in Renal Cystic Diseases

“…The characteristic clinical feature of PKD is hypertension resulting from the activation of intrarenal renin-angiotensin-aldosterone system. The cystic epithelial and tubular cells produce renin, angiotensinogen and angiotensin II which are secreted into cystic fluid [27,28]. ADPKD, affecting one in 400-1000 individuals, is caused by mutations in two genes, PKD1 or PKD2 [29].…”

SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway

“…Autosomal dominant polycystic kidney disease is a complex disease, in which many genes and signaling pathways are altered, resulting in a heterogeneous molecular profile (Malekshahabi et al, 2019), and this heterogeneity contributes to the clinical management of ADPKD patients (Bergmann et al, 2018). A broad range of signaling pathways have been identified to be involved in ADPKD development, including the cAMP, mammalian target of rapamycin (mTOR), Wnt, and Hippo-YAP signaling pathways (Bergmann et al, 2018).…”

“…Generally, ADPKD is caused by mutations in PKD1 or PKD2, which encode polycystin (PC)1 or PC2, respectively (Padovano and Podrini, 2018). Autosomal dominant polycystic kidney disease is characterized by the formation and development of numerous renal cysts, which result in the massive enlargement of the kidney and may eventually result in end-stage renal disease (Wilson, 2004;Malekshahabi et al, 2019). Limited therapeutic options are currently available for ADPKD; thus, identifying the deregulated molecular targets and pathways that are associated with disease progression are of great importance for the development of mechanism-based therapeutic strategies (LaRiviere et al, 2015).…”