Strategies targeting cAMP signaling in the treatment of polycystic kidney disease

Abstract

Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

Figure 1.

Diagram depicting putative pathways up- or downregulated in PKD. Dysregulation of [Ca2+]i and increased concentrations of cAMP play a central role. Increased accumulation of cAMP in polycystic kidneys may be explained the following hypotheses. (1) Reduced calcium activates calcium-inhibitable AC6, directly inhibits calcium/calmodulin-dependent PDE1 (by also increasing the levels of cGMP), and indirectly inhibits cGMP-inhibitable PDE3. (2) Dysfunction occurs in a ciliary protein complex (comprising A-kinase anchoring protein 150, AC5/6, polycystin-2, PDE4C, and PKA), which normally restrains cAMP signaling through inhibition of AC5/6 activity by polycystin-2–mediated calcium entry and degradation of cAMP by PDE4C transcriptionally controlled by HNF1β. (3) Depletion of the endoplasmic reticulum calcium stores trigger oligomerization and translocation of STIM1 to the plasma membrane, where it recruits and activates AC6. (4) Other contributory factors include disruption of PC1 binding to heterotrimeric G proteins, upregulation of the vasopressin V2 receptor, and increased levels of circulating vasopressin or accumulation of forskolin, lisophosphatidic acid, ATP, or other adenylyl cyclase agonists in the cyst fluid. Increased cAMP levels disrupt tubulogenesis, stimulate chloride and fluid secretion, and activate proproliferative signaling pathways, including mitogen-activated protein kinase/extracellularly-regulated kinase (in an Src- and Ras-dependent manner), mTOR, and β-catenin signaling. Activated mTOR transcriptionally stimulates aerobic glycolysis, increasing ATP synthesis and lowering AMP levels, which together with B-Raf–dependent activation of LKB1, inhibits AMPK, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion. PKA signaling also activates a number of transcription factors, including STAT3. Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors that, in turn, activates STAT3 on interstitial alternatively activated (M2) macrophages, which results in a feedforward loop between cyst-lining cells and M2 macrophages. Aberrant integrin–extracellular membrane interaction and cAMP signaling within focal adhesion complexes may contribute to the increased adhesion of cyst-derived cells to laminin-322 and collagen. AC-VI, adenylate cyclase 6; AMPK, AMP kinase; AVP, arginine vasopressin; B-Raf, B rapidly accelerated fibrosarcoma kinase; CDK, cyclin-dependent kinase; cGMP, cyclic guanosine monophosphate; CREB, cAMP response element binding transcription factor; ER, endoplasmic reticulum; GSK3β, glycogen synthase kinase 3β; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; Pax2, paired box gene 2; PC1, polycystin-1; PC2, polycystin-2; SST, somatostatin; SSTR, somatostatin receptor; STIM1, stromal interaction molecule 1.

Figure 2.

Tolerability and efficacy during the titration phase of TEMPO2:4. In the initial 2 months of the TEMPO2:4 study, a split-dose regimen of oral tolvaptan (8:00 AM/4:00 PM) was uptitrated (15/15, 30/15, 45/15, 60/30, and 90/30 mg/d) until tolerability was reached. Tolerability was defined as self-reported tolerance of a specific dose regimen by responding yes to the question: “Could you tolerate taking this dose of tolvaptan for the rest of your life?” Efficacy was defined by the capacity to suppress the action of vasopressin on the kidney reflected by sustained urine hypotonicity (Uosm<300 mOsm/kg). Reprinted from Higashihara et al., with permission.

Figure 3.

Effect of tolvaptan on primary (change in kidney volume) and secondary (time to multiple events of ADPKD and change in kidney function) results. (A) Slopes of total kidney volume growth (percent change from baseline). (B) Hazard ratio effects of tolvaptan on composite time to multiple events of ADPKD and its components. (C) Slopes of kidney function estimated by reciprocal serum creatinine. TOL denotes tolvaptan (blue). PBO denotes placebo (red). Reprinted from Torres et al., with permission.