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

Ronak Lakhia, Harini Ramalingam, Chun-Mien Chang, Patricia Cobo-Stark, Laurence Biggers, Andrea Flaten, Jesus Alvarez, Tania Valencia, Darren P. Wallace, Edmund C. Lee and Vishal Patel ()
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Ronak Lakhia: UT Southwestern Medical Center
Harini Ramalingam: UT Southwestern Medical Center
Chun-Mien Chang: UT Southwestern Medical Center
Patricia Cobo-Stark: UT Southwestern Medical Center
Laurence Biggers: UT Southwestern Medical Center
Andrea Flaten: UT Southwestern Medical Center
Jesus Alvarez: UT Southwestern Medical Center
Tania Valencia: Regulus Therapeutics Inc.
Darren P. Wallace: University of Kansas Medical Center
Edmund C. Lee: Regulus Therapeutics Inc.
Vishal Patel: UT Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-022-32543-2

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