Polycystic kidney diseases: from molecular discoveries to targeted therapeutic strategies

Abstract

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.

Figure 1

The structure of polycystin-1, polycystin-2 and fibrocystin (LRR, leucine-rich repeats; WSC, cell wall integrity and stress response component 1; PKD (Ig-like), Ig-like domains; LDL, low density lipoprotein domain; REJ, receptor for egg jelly; GPS, proteolytic G protein-coupled receptor proteolytic site; PLAT, lipoxygenase domain; EF, EF hand domain; TIG, immunoglobulin-like domains; TMEM2, homology with TMEM2 protein). Polycystin-1 and fibrocystin undergo cleavage at sites shown by the arrows.

Figure 2

Polycystin-1 in cell-cell/matrix adhesion in normal and ADPKD epithelia. (a) Polycystin-1 (PC-1) mediates cell-cell adhesion through homophilic interactions of its Ig-like domains. It localizes with desmosomal junctions (DJs) and adherens junctions (AJs). The components of DJs are shown: desmoplakin (Dp), desmogleins (Dsg), desmocollins (Dsc) and plakoglobin (Pg) [121]. AJs consist of E-cadherin (E-cad) as well as α, β and γ-catenins (catenins). The AJ complex provides a linkage to the actin cytoskeleton, and DJ link together intermediate filaments (IF) of epithelial cells. In ADPKD epithelial cells, dysfunctional PC-1 (crossed red lines) and desmosomal proteins are lost from cell-cell contacts and remain in intracellular vesicles. In addition, E-cadherin expression is reduced, resulting in compensatory expression of N-cadherin (N-cad). Thus, AJs and DJs are disrupted in ADPKD cells, while tight junctions (TJ) remain intact. (b) Expression of PC-1 in cell-matrix focal adhesion contacts. In normal epithelial cells, PC-1 is found in a complex with talin (TAL), paxillin (PAX), vinculin (VINC), focal adhesion kinase (FAK), c-src (SRC), p130-cas (CAS), nephrocystin (NPH1) and tensin (TEN). InADPKD cells, expression of FAK is lost from the focal adhesion complex.

Figure 3

Ciliary functions of cystoproteins: mechanosensation and cell cycle control. Polycystin-1 (PC-1), polycystin-2 (PC-2) and other cystoproteins (not shown) are expressed in primary cilia, basal bodies or centrosomes. The primary cilium forms in fully differentiated cells in the G0 phase of the cell cycle. A cilium protrudes from the basal body (centrosome) formed by two centrioles, a mother centriole (blue cylinder) and a daughter centriole (orange cylinder). As cells enter the cell cycle, the cilium is resorbed, and the centrosome can act as a mitotic spindle pole organizer. Flow-induced bending of cilia in renal epithelial cells triggers Ca²⁺ influx mediated by PC-2 in association with PC-1.The role of ciliary proteins in cell cycle control is supported by several findings: (1) In the normal state, PC-2 sequesters Id2 [proproliferative helix-loop-helix (HLH) protein] in the cytoplasm, preventing it from entering the nucleus. In PKD, when PC-1 or PC-2 are inactivated, Id2 translocates to the nucleus and interacts with E-protein, blocking its ability to induce growth-suppressive genes and resulting in increased activity of cdk2 and activation of cell proliferation; (2) PC-1 can activate the JAK/STAT signaling pathway, resulting in the induction of p21^waf1 and cell cycle arrest in G0 and G1; (3) The intraflagellar transport component IFT88/polaris is capable of controlling G1/S transition of the cell cycle. IFT88/polaris remains associated with the centrosome throughout the cell cycle, where it forms a complex with Che-1, thus modulating its binding to Rb protein.

Figure 4

Drug discovery platforms for anti-cystic therapeutic agents. High-throughput drug screening (HTS) of a small compound library can be performed using an in vitro assay of cystogenesis. Identified hits (active drugs) can then be rapidly assayed for preliminary efficacy and organ toxicity using a readily available cystic kidney organ culture assay that utilizes Pkd1^−/− animals. Effective compounds can be selected for in vivo efficacy testing in animal models of PKD. Further optimization of compounds using medicinal chemistry and SAR (structure-activity relationship) can proceed through the same screening platforms. The discovery process can also be initiated through “proof of concept” in vivo testing (drug candidate validation), followed by the drug optimization cycle.