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 ensues when the 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 cis-repressed via their 3-UTR miR-17 binding element. Eliminating this motif (Pkd1{Delta}17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also autoinhibited via its 3-UTR miR-17 motif, and Pkd2{Delta}17-induced Polycystin-2 derepression partly compensates and retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, PKD1{Delta}17 or PKD2{Delta}17 alleles revert cyst-pathogenic sequala in patient-derived primary ADPKD cultures. Thus, evading 3-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.