Novel targets for the treatment of autosomal dominant polycystic kidney disease

Abstract

Importance of the field: Autosomal dominant (AD) polycystic kidney disease (PKD) is the most common life-threatening hereditary disorder. There is currently no therapy that slows or prevents cyst formation and kidney enlargement in humans. An increasing number of animal studies have advanced our understanding of molecular and cellular targets of PKD.

Areas covered in the review: The purpose of this review is to summarize the molecular and cellular targets involved in cystogenesis and to update on the promising therapies that are being developed and tested based on knowledge of these molecular and cellular targets.

What the reader will gain: Insight into the pathogenesis of PKD and how a better understanding of the pathogenesis of PKD has led to the development of potential therapies to inhibit cyst formation and/or growth and improve kidney function.

Take home message: The results of animal studies in PKD have led to the development of clinical trials testing potential new therapies to reduce cyst formation and/or growth. A vasopressin V2 receptor antagonist, mTOR inhibitors, blockade of the renin-angiotensin system and statins that reduce cyst formation and improve renal function in animal models of PKD are being tested in interventional studies in humans.

Figure 1. Schematic representation of the various molecular pathways up- or downregulated in polycystic kidney disease

Potential targets for inhibition are depicted in light gray boxes. Potential inhibitors are depicted in clear boxes. The cAMP pathway promotes cell proliferation and fluid secretion in PKD. cAMP leads to fluid secretion via the CFTR. cAMP results in activation of the ERK-MAPK pathway leading to cell proliferation. cAMP accumulation is promoted by mechanisms of dysregulation of PC1 or PC2, as well as inhibition of Ca²⁺-dependent phosphodiesterase (PDE). Caffeine inhibits PDE, which normally degrades cAMP. Thus, caffeine results in an increase in cAMP. cAMP signaling also requires PKA, Src and Ras. Src is known to activate Ras. Activation of tyrosine kinase receptors also contributes to the stimulation of MAPK-ERK signaling with consequent cell proliferation. Potential therapeutic targets are the vasopressin V2 receptor, tyrosine kinases, MEK and c-Src. The PI3K-Akt pathway plays a major role in mTOR signaling (see Figure 2); mTOR inhibitors bind to FKBP, which subsequently inhibits mTOR. There is evidence for activation of the mTOR pathway in ADPKD. The RAAS (see Figure 3) is activated by a drop in renal perfusion that stimulates the JGA to make renin. ACE inhibitors block the conversion of angiotensin I to angiotensin II. Renin inhibitors directly block renin production by the JGA. Angiotensin receptor blockers block the ATIIR. There is evidence for activation of the RAAS in ADPKD patients. ACE: Angiotensin-converting enzyme; AGT1: Angiotensin 1; ARB: Angiotensin receptor blocker; ATIIR: Angiotensin II receptor; Ca²⁺: Intracellular calcium; cAMP: Cyclic adenosine monophosphate; CDK: Cyclin-dependent kinase; CFTR: Cystic fibrosis transmembrane conductance regulator; EGF: Epidermal growth factor; ERK: Extracellular signal-regulated kinase; FKBP: FK506 binding protein; Gi,Gs: G protein; HMG-CoAR: 3-hydroxy-3-methyl-glutaryl-CoA reductase; IGF: Insulin-like growth factor; JGA: Juxtaglomerular apparatus; MAPK: Mitogen–activated protein kinase; MEK: Maperk kinase; mTOR: Mammalian target of rapamycin; PI3K: Phosphoinositide 3-kinase; PC1: Polycystin1; PC2: Polycystin2; PDE: Phosphodiesterase; PKA: Protein kinase A; Rheb: Ras homolog enriched in brain; Src: Sarcoma; SSTR: Somatostatin receptor; TKI: Tyrosine kinase inhibitor; TNF: Tumor necrosis factor; V2R: Vasopressin v2 receptor; VEGF: Vascular endothelial growth factor.

Figure 2. The PI3K-AKT pathway plays a major role in mTOR signaling

PI3K converts the lipid PIP₂ into PIP₃ (Phosphatidylinositol (3,4,5)-trisphosphate), which localizes AKT to the membrane. The tuberous sclerosis complex 1 (TSC1; hamartin) and TSC2 (tuberin) complex is inactivated by AKT-dependent phosphorylation. Inactivation of TSC2 results in activation of mTOR via the Ras-related small GTPase (Rheb). mTOR phosphorylates p70S6K1, resulting in cell proliferation. mTOR inhibitors bind to FKBP (FK506 binding protein), which subsequently inhibits mTOR. There is evidence for activation of the mTOR pathway in ADPKD.

Figure 3. The renin–angiotensin–aldosterone system (RAAS)

The RAAS is activated by a drop in renal perfusion that stimulates the JGA to make renin. ACE inhibitors block the conversion of angiotensin 1 to angiotensin II. Renin inhibitors directly block renin production by the JGA. Angiotensin receptor blockers block the ATIIR. There is evidence for activation of the RAAS in ADPKD patients. Potential therapeutic targets in PKD are ACE, the angiotensin receptor and renin. ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; JGA: Juxtaglomerular apparatus.