PKHD1 post‐transcriptionally modulated by miR‐365‐1 inhibits cell‐cell adhesion

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a severe inherited disorder with an incidence of 1/20 000 live births. Mutations of PKHD1 (polycystic kidney and hepatic disease gene 1) gene were identified to be responsible for ARPKD. However, the underlying molecular mechanisms remain largely unknown. MicroRNAs (miRNAs) are an abundant class of small RNAs with global effect on gene expression. Up to 30% of human protein coding genes may be regulated by miRNAs. However, to date, nothing is known regarding the role of miRNAs in PKHD1. In this study, we exploited bioinformatics to analyse the 3'UTR of PKHD1 gene and illustrated that the 3'UTR region of the gene is highly conserved in evolution. We identified about 35 candidate miRNAs within a 3738 bp window of the 3'UTR region. Of the 35 potential miRNAs, miR-365-1 emerged to post-transcriptionally modulate the expression of PKHD1. Furthermore, we demonstrated that miR-365-1 modulated PKHD1 suppressed cell-cell adhesion in part through E-cadherin.

Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases

“…PKHD1 was found to be a direct target of miR-365-1 (35). Polycystic liver disease, a frequent feature of PKD, is associated with a reduction in miR-15a expression (79).…”

MicroRNAs and their applications in kidney diseases

“…Further studies are required to relate these findings to the role of miR-15a in ARPKD. Finally, miR-365-1 has been recently shown to inhibit the expression of Polycystic Kidney and Hepatic Disease 1 (PKHD1) [90], however, further studies are required to fully elucidate the role miR-365-1 within ARPKD.…”

The regulation and function of micrornas in kidney diseases

“…Another subtype of PKD, autosomal recessive PKD (ARPKD), can be caused by mutation of polycystic kidney and hepatic disease 1 (PKHD1). Bioinformatic analysis of the 3′‐UTR of PKHD1 and luciferase assay suggested that PKHD1 is a direct target of mir‐365‐1 and its function might involve the decrease of E‐cadherin and destruction of the ECM . PKD frequently associates with polycystic liver diseases.…”