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Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases

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

  • Renal cysts of tubular epithelial cell origin are a hallmark of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)

  • Causative genetic loci are the polycystin-encoding PKD1 and PKD2 for ADPKD, and the fibrocystin-encoding PKHD1 for ARPKD

  • Disruption of these proteins in tubular epithelia causes de-differentiation, excessive fluid secretion, and proliferation, leading to cyst development

  • Cellular components and processes implicated in ADPKD and ARPKD include cilia, Wnt, calcium homeostasis, cyclic AMP, RAS/MAPK and concentrating capacity

  • 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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Figure 1: Cellular phenotypic abnormalities caused by PKD mutations.
Figure 2: Model of mechanosensation and control of differentiation of tubular epithelium by urine flow and calcium fluxes.
Figure 3: Polycystin function and possible downstream effects of disrupting the polycystin pathway: alterations of [Ca2+]i homeostasis.
Figure 4: Polycystin function and possible downstream effects of disrupting the polycystin pathway: upregulation of cyclic AMP signaling.
Figure 5: Polycystin function and possible downstream effects of disrupting the polycystin pathway: upregulation of Ras–MAPK signaling.
Figure 6: Polycystin function and possible downstream effects of disrupting the polycystin pathway: reduced renal concentrating capacity.

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Correspondence to Vicente E Torres.

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VE Torres has received research grant support from Otsuka Pharmaceutical Company.

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ADPKD

ARPKD

PKD1

PKD2

PKHD1

Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease

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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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