Scholz Julia Katharina, Kraus Andre, Lüder Dominik, Skoczynski Kathrin, Schiffer Mario, Grampp Steffen, Schödel Johannes, Buchholz Bjoern
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuernberg, Ulmenweg 18, 91054 Erlangen, Germany.
Faculty of Computer Science, University of Applied Sciences, Augsburg, Germany.
iScience. 2022 May 5;25(6):104359. doi: 10.1016/j.isci.2022.104359. eCollection 2022 Jun 17.
Autosomal dominant polycystic kidney disease is the most common monogenic disease that causes end-stage renal failure. It primarily results from mutations in the PKD1 gene that encodes for Polycystin-1. How loss of Polycystin-1 translates into bilateral renal cyst development is mostly unknown. cAMP is significantly involved in cyst enlargement but its role in cyst initiation has remained elusive. Deletion of Polycystin-1 in collecting duct cells resulted in a switch from tubule to cyst formation and was accompanied by an increase in cAMP. Pharmacological elevation of cAMP in Polycystin-1-competent cells caused cyst formation, impaired plasticity, nondirectional migration, and mis-orientation, and thus strongly resembled the phenotype of Polycystin-1-deficient cells. Mis-orientation of developing tubule cells in metanephric kidneys upon loss of Polycystin-1 was phenocopied by pharmacological increase of cAMP in wildtype kidneys. , cAMP impaired tubule formation after capillary-induced injury which was further impaired by loss Polycystin-1.
常染色体显性多囊肾病是导致终末期肾衰竭的最常见单基因疾病。它主要由编码多囊蛋白-1的PKD1基因突变引起。多囊蛋白-1的缺失如何转化为双侧肾囊肿的形成大多尚不清楚。环磷酸腺苷（cAMP）在囊肿增大过程中起重要作用，但其在囊肿起始阶段的作用仍不清楚。集合管细胞中多囊蛋白-1的缺失导致从肾小管到囊肿的转变，并伴有cAMP增加。在具有正常多囊蛋白-1的细胞中，通过药物提高cAMP会导致囊肿形成、可塑性受损、无定向迁移和方向错误，因此与多囊蛋白-1缺陷细胞的表型极为相似。在多囊蛋白-1缺失后，后肾中发育中的肾小管细胞方向错误，而在野生型肾脏中通过药物增加cAMP可模拟这一现象。此外，cAMP会损害毛细血管诱导损伤后的肾小管形成，而多囊蛋白-1的缺失会进一步加剧这种损害。
