Abstract
Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the best known of a large family of inherited diseases characterized by the development of renal cysts of tubular epithelial cell origin. Autosomal dominant and recessive polycystic kidney diseases have overlapping but distinct pathogeneses. Identification of the causative mutated genes and elucidation of the function of their encoded proteins is shedding new light on the mechanisms that underlie tubular epithelial cell differentiation. This review summarizes recent literature on the role of primary cilia, intracellular calcium homeostasis, and signaling involving Wnt, cyclic AMP and Ras/MAPK, in the pathogenesis of polycystic kidney disease. Improved understanding of pathogenesis and the availability of animal models orthologous to the human diseases provide an excellent opportunity for the development of pathophysiology-based therapies. Some of these have proven effective in preclinical studies, and clinical trials have begun.
Key Points
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Renal cysts of tubular epithelial cell origin are a hallmark of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)
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Causative genetic loci are the polycystin-encoding PKD1 and PKD2 for ADPKD, and the fibrocystin-encoding PKHD1 for ARPKD
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Disruption of these proteins in tubular epithelia causes de-differentiation, excessive fluid secretion, and proliferation, leading to cyst development
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Cellular components and processes implicated in ADPKD and ARPKD include cilia, Wnt, calcium homeostasis, cyclic AMP, RAS/MAPK and concentrating capacity
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Preclinical trials in animal models are testing antiproliferative agents, agonists of peroxisome proliferative activated receptor gamma, inhibitors of epidermal growth factor receptor tyrosine kinases and antagonists of vasopressin V2 receptors
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VE Torres has received research grant support from Otsuka Pharmaceutical Company.
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Torres, V., Harris, P. Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases. Nat Rev Nephrol 2, 40–55 (2006). https://doi.org/10.1038/ncpneph0070
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DOI: https://doi.org/10.1038/ncpneph0070
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