Molecular advances in autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. The understanding of the pathogenesis of ADPKD has advanced significantly since the discovery of the 2 causative genes, PKD1 and PKD2. Dominantly inherited gene mutations followed by somatic second-hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a nonmotile microtubule-based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell-signaling pathways that have been implicated in the pathways related to PKD1 and PKD2.

Figure 1. Structures of polycystin-1 and polycystin-2

Thick green line represents the membrane bilayer. The protein motifs are identified in the boxed figure legend. Light blue and green cylinders represent putative transmembrane segments. Structures are not drawn to scale.

Figure 2. Threshold model of cyst formation in ADPKD

This model is based on the hypothesis that a critical level of PKD1 and PKD2 functional activity is required to form and maintain tubule structure (solid red line). In this model, a cyst forms when the combined activity of two alleles falls below the specific threshold for an individual cell. The requisite threshold may be vary based on a combination of factors such as genetic variants at modifier loci, environmental effects, the developmental stage of the kidney, or physiologic demands such as in response to injury (dashed red lines). The actual of level of activity achieved is determined by the specific combination of allelic variants in a gene, e.g., PKD1. In this example, three different wild type variant alleles (WT1–WT3) have their own unique set of polymorphisms that impact PKD1 activity with WT1 having the greatest activity. Combinations of wild type alleles with each other or with a null allele provide sufficient activity to avert cyst growth (leftmost three columns). Mutant alleles have less activity than the wild type variants. These range from complete loss of function (Null) to missense mutations with reduced activity (Miss, Miss-1, Miss-2). Individuals who inherit any of these hypomorphic, reduced function, allele haplotypes through the germline may acquire somatic mutations in individual cells (rightmost six columns) that in combination may fall below cell-specific threshold levels of activity and lead to cyst formation. In the illustration, Null/Null and Null/Miss-2 allele combinations will invariably result in cysts, whereas Miss/Miss-1 will never result in cysts with the other combinations having different effects depending on the actual cellular thresholds. This model also applies to PKD2.

Figure 3. Phenotypic response to acquired Pkd1 loss is exquisitely sensitive to developmental life stage

A, Kidneys of Pkd1^cond/cond;tamoxifen-Cre+ mice with inactivation of Pkd1 induced at postnatal day 12 (P12) became cystic within 3 weeks (left panel), whereas if Pkd1 inactivation occurs at P14, they remained normal 3 months later (right panel) [from (55)]. B,C, Pkd1 inactivation in adult kidneys results in late-onset renal cystic disease. Kidneys from Pkd1^cond/cond;tamoxifen-Cre+ mice harvested 3 months (B) or 6 months (C) after Pkd1 inactivation was induced at 6 weeks of age [from (55)].

Figure 4. Subcellular localization of “cystoproteins”

Numerous proteins associated with cystic kidneys (“cystoproteins”) localize to the primary cilium and basal body complex but are also found in other intracellular compartments. AJ, adherens junction; BB, basal body; Cen, centriole; ER, endoplasmic reticulum; FAP, focal adhesion plaque; TJ, tight junction. [Adapted from (67) and Menezes and Germino, Methods in Cell Biology 94: 273–297, 2009].

Figure 5. Planar cell polarity and tubular morphogenesis

Planar cell polarity may help to establish normal tubular architecture through directional cell division (top left) and convergent extension/directional cell migration (bottom left). Disruption of these processes could potentially result in cyst formation (right). [Adapted from (96) and Menezes and Germino, Methods in Cell Biology 94: 273–297, 2009].