Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context

Abstract

Patients with autosomal dominant polycystic kidney disease (ADPKD) typically carry a mutation in either the PKD1 or PKD2 gene, which leads to massive cyst formation in both kidneys. However, the large intrafamilial variation in the progression rate of ADPKD suggests involvement of additional factors other than the type of mutation. The identification of these factors will increase our understanding of ADPKD and could ultimately help in the development of a clinically relevant therapy. Our review addresses the mechanisms by which various biologic processes influence cyst formation and cyst growth, thereby explaining an important part of the inter- and intrafamilial variability in ADPKD. Numerous studies from many laboratories provide compelling evidence for the influence on cyst formation by spatiotemporal gene inactivation, the genetic context, the metabolic status, the presence of existing cysts, and whether the kidneys were challenged by renal injury. Collectively, a solid basis is provided for the concept that the probability of cyst formation is determined by functional PKD protein levels and the biologic context. We model these findings in a graphic representation called the cystic probability landscape, providing a robust conceptual understanding of why cells sometimes do or do not form cysts.

Keywords: ADPKD; Biological Context; PKD1; Polycystin; Probability Landscape; polycystic kidney disease.

Figure 1.

Timing and location of Pkd1 inactivation, cysts, and macrophages influencing the PKD phenotype. (A) The pattern of Cre activity was determined by crossbreeding the tamoxifen (Tam)–inducible iKsp-Pkd1^del mice with an LacZ reporter strain (lower panel). A similar pattern of Cre activity was revealed by LacZ staining of kidneys from mice that received Tam at either P10–P12 (P10) or P18–P20 (P18). However, despite this similar pattern of Cre activity, Tam administration at these different ages dramatically affected the progression rate of cyst formation: hematoxylin and eosin–stained kidney sections are shown (upper panel) from an iKsp-Pkd1^del mouse euthanized 3 weeks after Tam administration at P10–P12 (P10) and an iKsp-Pkd1^del mouse euthanized 10 weeks after Tam at P18–P20 (P18). Also, the tubular origin in which Pkd1 is inactivated seems to influence susceptibility. This is especially prominent in the P10 model, in which the outer medulla (OM) is the most severely affected region; however, this region has the fewest Pkd1–deficient cells. (B) iKsp-Pkd1^del mice had been treated with low-dose Tam at P40 (leading to Pkd1 inactivation in about 8% of cells) and were euthanized at an age of 9 months. Kidneys were harvested and stained with anti-F4/80 (brown), which in mouse studies, is frequently used as a general marker for macrophages. Whole-kidney sections stained with anti-F4/80 are shown from an iKsp-Pkd1^del mouse at a relatively mild stage of PKD (upper left panel) and an iKsp-Pkd1^del mouse at a somewhat more advanced stage of PKD (lower left panel). Both mice show clusters of cysts but still had normal kidney function on the basis of measurements of the urea concentration in blood. Enlargements of F4/80 images are shown in right panel. The wild–type (WT) kidney image was taken from an anti–F4/80–stained kidney section from an age–matched WT control mouse. Images 1–3 are enlargements of the areas indicated in the whole sections. In regions not affected by cyst formation (image 2), F4/80 staining is comparable with that in the WT kidney. Regions with cysts (images 1 and 3) show increased F4/80 staining in the interstitial compartment around normal and slightly dilated tubules. C, cortex; IM, inner medulla.

Figure 2.

The cystic probability landscape of renal epithelial cells. (A) Each situation requires a certain level of expression of functional PKD proteins to ensure normal homeostasis (left panel). When the expression deviates from the normal situation, the expression is either too low or too high (x axis). The extent to which certain biologic processes influence the probability of cyst formation is depicted on the z axis. Sometimes the effect is very low, such as the biologic context of an adult kidney, and sometimes the effect can be very high, such as the biologic context of a developing kidney. The combination of the PKD protein expression levels (x axis) and the particular biologic context (z axis) will determine a certain probability of cyst formation, which is indicated on the y axis. The combination of all theoretical possible situations results in the cystic probability landscape. The circles indicate examples of locations of renal epithelial cells within the landscape (the circle size correlates to how frequently such situations might occur; right panel). Throughout life, renal epithelial cells from healthy individuals will undergo certain biologic processes (examples are indicated in boxes). However, because PKD protein expression levels (for these examples, PKD1 expression is indicated for simplicity) are properly regulated in these cells, the probability that these cells will form cysts is low. (B) Throughout life, renal epithelial cells from patients with ADPKD move differently within the landscape. During renal development (Developm.), most cells have a heterozygous PKD1 mutation (PKD1^+/−), but generally, these cells do not form cysts unless some cells also lose the second allele (PKD1^−/−; left panel). Also, cells that have two hypomorphic alleles of PKD1 (PKD1 hypo.) have a high risk of developing cysts. Although the probability of cyst formation increases when a cell loses PKD1 during adulthood or has two PKD1 hypo., cyst formation is rare under physiologic conditions (center panel). However, during an episode of local renal injury, PKD1^−/− cells have a much higher probability to form cysts. Also, overexpression of PKD1 (PKD1⁺⁺⁺) leads to increased probability of cyst formation. As PKD progresses, the number and size of cysts increase, leading to injury-like responses caused by the existing cysts themselves, infiltrating cells, etc. (right panel). This leads to changes in the biologic context of resident PKD1–deficient cells and generally, situations with increased risk of cyst formation. Ultimately, these various biologic processes will push renal epithelial cells with aberrant PKD1 expression toward the higher regions of the probability landscape, causing additional increase in the numbers of cysts.