Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1's C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration-approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.

Ketogenic dietary interventions in autosomal dominant polycystic kidney disease-a retrospective case series study: first insights into feasibility, safety and effects.

Background: Our laboratory published the first evidence that nutritional ketosis, induced by a ketogenic diet (KD) or time-restricted diet (TRD), ameliorates disease progression in polycystic kidney disease (PKD) animal models. We reasoned that, due to their frequent use for numerous health benefits, some autosomal dominant PKD (ADPKD) patients may already have had experience with ketogenic dietary interventions (KDIs). This retrospective case series study is designed to collect the first real-life observations of ADPKD patients about safety, feasibility and possible benefits of KDIs in ADPKD as part of a translational project pipeline. Methods: Patients with ADPKD who had already used KDIs were recruited to retrospectively collect observational and medical data about beneficial or adverse effects and the feasibility and safety of KDIs in questionnaire-based interviews. Results: A total of 131 ADPKD patients took part in this study. About 74 executed a KD and 52 a TRD for 6 months on average. A total of 86% of participants reported that KDIs had improved their overall health, 67% described improvements in ADPKD-associated health issues, 90% observed significant weight loss, 64% of participants with hypertension reported improvements in blood pressure, 66% noticed adverse effects that are frequently observed with KDIs, 22 participants reported safety concerns like hyperlipidemia, 45 participants reported slight improvements in estimated glomerular filtration rate and 92% experienced KDIs as feasible while 53% reported breaks during their diet. Conclusions: Our preliminary data indicate that KDIs may be safe, feasible and potentially beneficial for ADPKD patients, highlighting that prospective clinical trials are warranted to confirm these results in a controlled setting and elucidate the impact of KDIs specifically on kidney function and cyst progression.