Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a genetic disorder with an incidence of ~1:20,000 that manifests in a wide range of renal and liver disease severity in human patients and can lead to perinatal mortality. ARPKD is caused by mutations in PKHD1, which encodes the large membrane protein, Fibrocystin, required for normal branching morphogenesis of the ureteric bud during embryonic renal development. The variation in ARPKD phenotype suggests that in addition to PKHD1 mutations, other genes may play a role, acting as modifiers of disease severity. One such pathway involves non-canonical Wnt/Planar Cell Polarity (PCP) signalling that has been associated with other cystic kidney diseases, but has not been investigated in ARPKD. Analysis of the AtminGpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of ARPKD. Further, modulation of Atmin affected Pkhd1 mRNA levels, altered non-canonical Wnt/PCP signalling and impacted cellular proliferation and adhesion, although Atmin does not bind directly to the C-terminus of Fibrocystin. Differences in ATMIN and VANGL2 expression were observed between normal human paediatric kidneys and age-matched ARPKD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human ARPKD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E-cadherin was also detected in ARPKD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in ARPKD and suggests ATMIN as a modulator of PKHD1.
Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as β-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that well-designed preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.
Increased activity of the intrarenal renin-angiotensinaldosterone system (RAAS) is the main pathogenic mechanism for the development of early hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD). Moreover, intrarenal RAAS is an important component for renal potassium handling and maintaining potassium balance. The recent HALT-PKD trial for ADPKD showed that episodes of hyperkalemia were infrequently observed despite dual blocking in RAAS. The aims of this study were to investigate whether high intrarenal RAAS activity affects serum potassium levels and whether it acts as a prognostic marker in patients with ADPKD. METHODS: This prospective longitudinal study was conducted with 1788 subjects from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). The baseline urinary angiotensinogen (AGT) level was measured using a commercially available enzyme-linked immunosorbent assay kit. Propensity score matching (PSM) analysis was performed to compare potassium handling between the ADPKD and non-PKD groups. The primary outcome of this study was the composite of all-cause mortality and renal function decline. RESULTS: Patients' mean age was 54.0 6 12.2 years, and 690 (38.6%) were women. The average estimated glomerular filtration rate was 50.1 6 29.9 mL/min/1.73 m 2. The risk of hyperkalemia was significantly lower in ADPKD than in other causes of chronic kidney disease after adjusting the covariables. In multivariable linear regression analysis, the urinary AGT/creatinine (Cr) ratio was negatively correlated with the serum potassium level (b ¼-0.058, P ¼ 0.017) and positively associated with the transtubular potassium gradient (TTKG, b ¼ 0.087, P ¼ 0.001). After PSM, patients with ADPKD had significantly lower serum potassium levels (P < 0.001) with oppositely elevated TTKGs (P ¼ 0.024). Additionally, the urinary AGT/Cr ratio was significantly higher in ADPKD than in non-PKD (P ¼ 0.003). These results were much prominent in the comparison between ADPKD and diabetic nephropathy. In 293 patients with ADPKD, the urinary AGT/Cr ratio was a significant risk factor of the composite outcome (hazard ratio, 1.33; 95% confidence interval, 1.10-1.62; P ¼ 0.004). CONCLUSIONS: Increasing activity of intrarenal RAAS represented by a high urinary AGT level is associated with high tubular potassium excretion and a low serum potassium level, and is a prognostic marker in patients with ADPKD. The present study suggests that a higher degree of RAAS blockade may be needed to inhibit intrarenal RAAS activity in patients with ADPKD.
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