Treatment strategies and clinical trial design in ADPKD

Abstract

More frequent utilization and continuous improvement of imaging techniques has enhanced appreciation of the high phenotypic variability of autosomal dominant polycystic kidney disease, improved understanding of its natural history, and facilitated the observation of its structural progression. At the same time, identification of the PKD1 and PKD2 genes has provided clues to how the disease develops when they (genetic mechanisms) and their encoded proteins (molecular mechanisms) are disrupted. Interventions designed to rectify downstream effects of these disruptions have been examined in animal models, and some are currently tested in clinical trials. Efforts are underway to determine whether interventions capable to slow down, stop, or reverse structural progression of the disease will also prevent decline of renal function and improve clinically significant outcomes.

Figure 1

Diagram depicting hypothetical mechanisms by which the polycystins directly affect gene transcription and regulate the cell cycle. PC1 binds and activates JAK2 in a PC2-dependent manner. JAK2 is a member of the Janus kinase family of tyrosine kinases which in turn phosphorylates and activates the transcription factor STAT-1, upregulating p21^waf (a cell cycle inhibitor), inhibiting cyclin-dependent kinase 2 (Cdk2), and inducing cell cycle arrest in G0/G1. PC2 binds Id2, a helix-loop-helix protein, and prevents its translocation to the nucleus and suppression of p21^waf, thus preventing Cdk2 activation and cell cycle progression. The C-terminal tail of PC1 can be cleaved and migrate to the nucleus. Two non-mutually exclusive models have been suggested. In the first, PC1 normally sequesters the transcription factor STAT6 on cilia thereby preventing its activation. Interruption of luminal fluid flow (e.g. after ureteral clamping or renal injury) triggers the cleavage of the final 112 amino acids. This p112 fragment interacts with STAT6 and the co-activator P100 and stimulates transcriptional activity. In the second, mechanical stimulation of the primary cilium normally triggers the cleavage and release of the entire C terminal tail (p200). This p200 fragment contains a nuclear localization motif, binds β-catenin in the nucleus, and inhibits its ability to activate T-cell factor-dependent gene transcription, a major effector of the canonical Wnt signaling pathway.

Figure 2

Diagram depicting hypothetical pathways up- or down regulated in polycystic kidney disease and rationale for treatment with V2R antagonists, somatostatin, triptolide; tyrosine kinase, src, MEK, TNFα, mTOR or CDK inhibitors; metformin, and CFTR or KCa3.1 inhibitors (drugs in pre-clinical trials only in green boxes; drugs in clinical trials in orange 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, since 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 AVP due to an intrinsic concentrating defect; (iv) upregulation of AVP V2Rs. 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 a 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. TNFα acting on its receptor activates IKKb (inhibitor of kB kinase-b), which phosphorylates hamartin, suppressing TSC1-TSC2 function and activating mTOR. Activation of AMPK may blunt cystogenesis via inhibition of CFTR, inhibition of ERK, and phosphorylation of tuberin and inhibition of mTOR. 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 release 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, AVP V2R; V2RA, AVP V2R antagonists.