Autosomal dominant polycystic kidney disease: the last 3 years

Abstract

Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective therapies. The purpose of this review is to update the core of knowledge in this area with recent publications that have appeared during 2006-2009.

Figure 1. Diagram of the PKD1 protein, polycystin-1 (left) and the PKD2 protein, polycystin-2, and their interaction through coiled-coil domains in the C-terminal tails (according to the revised molecular model)

Details of the domains and regions of homology are shown in the key. Recently, it has been proposed that polycystin-1 may activate transcription directly by cleavage and translocation of the C-terminus to the nucleus, a process found in other transmembrane proteins. The cleavage site in the GPS region and possible cleavage sites in the C-terminal tail of polycystin-1 are marked with arrows. TRP, transient receptor potential.

Figure 2. Diagram depicting putative pathways up- or downregulated in polycystic kidney disease and rationale for treatment with V2 receptor antagonists, somatostatin, triptolide; tyrosine kinase, src, MEK, TNFα, mTOR, or CDK inhibitors; metformin, and CFTR or KCa3.1 inhibitors (green boxes)

Dysregulation of [Ca²⁺]_i, increased concentrations of cAMP, mislocalization of ErbB receptors, and upregulation of EGF, IGF1, VEGF, and TNFα occur in cells/kidneys bearing PKD mutations. Increased accumulation of cAMP in polycystic kidneys may result from: (i) disruption of the polycystin complex, as PC1 may act as a Gi protein-coupled receptor; (ii) stimulation of Ca²⁺ inhibitable AC6 and/or inhibition of Ca²⁺-dependent PDE1 by a reduction in [Ca²⁺]_i; (iii) increased levels of circulating vasopressin due to an intrinsic concentrating defect; and/or (iv) upregulation of vasopressin V2 receptors. Increased cAMP levels contribute to cystogenesis by stimulating chloride and fluid secretion. In addition, cAMP stimulates mitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling and cell proliferation in an Src- and Ras-dependent manner in cyst-derived cells or in wild-type tubular epithelial cells treated with Ca²⁺ channel blockers or in a low Ca²⁺ medium. Activation of tyrosine kinase receptors by ligands present in cystic fluid also contributes to the stimulation of MAPK/ERK signaling and cell proliferation. Phosphorylation of tuberin by ERK (or inadequate targeting to the plasma membrane due to defective interaction with polycystin-1) may lead to the dissociation of tuberin and hamartin and lead to the activation of Rheb and mTOR. Upregulation of TNFα or downregulation of AMPK signaling may also stimulate mTOR signaling through inhibition of the tuberin–hamartin complex. Activation of AMPK may also blunt cystogenesis through inhibition of CFTR and ERK. Upregulation of Wnt signaling stimulates mTOR and β-catenin signaling. ERK and mTOR activation promotes G1/S transition and cell proliferation through regulation of cyclin D1, phosphorylation of retinoblastoma protein (RB) by CDK4/6-cyclin D and CDK2-cyclin E, and the release of the E2F transcription factor. AC-VI, adenylate cyclase 6; AMPK, AMP kinase; CDK, cyclin-dependent kinase; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PC1, polycystin-1; PC2, polycystin-2; PDE, phosphodiesterase; PKA, protein kinase A; R, somatostatin sst2 receptor; TSC, tuberous sclerosis proteins tuberin (TSC2) and hamartin (TSC1); V2R, vasopressin V2 receptor; V2RA, vasopressin V2 receptor antagonists.