Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression.
Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression.
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DOI：
10.1073/pnas.2121267119
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发表时间：
2022-07-26
影响因子：
11.1
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常染色体显性遗传性多囊肾病（ADPKD）是一种遗传性疾病，通常由多囊蛋白-1突变引起。这种疾病与严重的发病率有关，治疗选择有限，大多数患者在60岁之前需要透析或移植。我们的工作通过阐明PKC β在ADPKD中的作用和将PKC β作为潜在的治疗靶点，增加了对多囊肾病（PKD）发病机制的理解。我们发现，PKC β磷酸化多囊蛋白-1在两个特定的丝氨酸残基。我们证明，PKC β在人类ADPKD和PKD小鼠模型中异常下调，并且其活性可以通过美国食品和药物管理局批准的药物FTY 720治疗恢复。最后，我们证明FTY 720治疗可改善PKD小鼠模型的疾病进展，并且这些改善依赖于PKC β的表达。常染色体显性遗传性多囊肾病（ADPKD）仅在美国就影响超过50万人。在大多数情况下，ADPKD是由PKD 1基因中的功能缺失突变引起的，该基因编码多囊蛋白-1（PC 1）。以往的研究报道，PC 1与非典型蛋白激酶C（aPKC）相互作用。在这里，我们表明，PC 1结合的α PKC（PKC β）的β亚型，并确定两个PKC β磷酸化位点上PC 1的C-末端尾巴。在ADPKD患者以及正性和非正性PKD小鼠模型中，PKC β的表达下调。我们发现，美国食品和药物管理局批准的药物FTY 720在多囊肾病（PKD）的体外和体内模型中恢复PKC β的表达，这与多种PKD小鼠模型中疾病进展的改善相关。重要的是，我们表明FTY 720治疗在这些PKD小鼠模型的PKC β无效版本中效果较差，阐明了PKC β特异性作用机制，包括抑制STAT 3活性和囊肿衬里细胞增殖。综上所述，我们的研究结果表明，PKC β下调是PKD的标志，FTY 720稳定PKC β可能代表治疗该疾病的治疗方法。
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder commonly caused by mutations in polycystin-1. The disease is associated with severe morbidity and has limited therapeutic options, with most patients requiring dialysis or transplantation by the sixth decade. Our work adds to understanding polycystic kidney disease (PKD) pathogenesis by clarifying the role of PKCζ in ADPKD and by presenting PKCζ as a potential therapeutic target. We show that PKCζ phosphorylates polycystin-1 at two specific serine residues. We demonstrate that PKCζ is aberrantly down-regulated in human ADPKD and mouse models of PKD and that its activity can be restored via treatment with the US Food and Drug Administration–approved drug FTY720. Last, we demonstrate that FTY720 treatment ameliorates disease progression in PKD mouse models and that these improvements are dependent on PKCζ expression. 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.