PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3'-UTR miR-17 binding element. Eliminating this motif (Pkd1^∆17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3'-UTR miR-17 motif, and Pkd2^∆17-induced Polycystin-2 derepression retards cyst growth in Pkd

SUBMITTER: Lakhia R 

PROVIDER: S-EPMC9376183 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature