PKD1

Internal medicine

Endocrinology

Chemistry

Kidney disease

Disease

Polycystic kidney disease

Polycystic kidney

Genetics

Bioinformatics

Medicine

Biology

Nature Communications

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 Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1∆17 or PKD2∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3′-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach. ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.

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