Kidney Week

Abstract: TH-PO695

Deletion of miR-214 Skews Macrophage Polarization to Promote Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

• ADPKD: Genetic and Model Studies
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Lakhia, Ronak, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Ronak Lakhia,

• Yheskel, Matanel, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Matanel Yheskel,

• Flaten, Andrea N., University of Texas Southwestern Medical Center, Dallas, Texas, United States

Andrea N. Flaten,

• Aboudehen, Karam S., University of Minnesota, Minneapolis, Minnesota, United States

Karam S. Aboudehen,

• Patel, Vishal, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Vishal Patel,

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by fluid-filled cysts that arise from kidney tubules and compress functioning nephrons leading to kidney failure. MicroRNAs (miRs) are small non-coding RNAs that can regulate gene expression. Our understanding of the role microRNAs in ADPKD is limited. The goal of this study was to understand the role of miR-214 in ADPKD.

Methods

Q-PCR and in situ hybridization were performed to analyze the expression of miR-214 and its host lncRNA transcript, Dnm3os (Dynamin 3 opposite strand), in mouse and human ADPKD. Next, we genetically deleted miR-214 expression in Pkhd1/Cre; Pkd2^F/F (Pkd2-KO) mice and Pkd1^RC/RC mice, two genetic models of ADPKD. Kidney mRNA sequencing and pathway analysis was performed to elucidate the differential gene expression pattern between Pkd2-KO and Pkd2-miR-214^-/- double KO mice. In vitro, mIMCD3 and RAW264.7 cells were treated with miR-214 mimics.

Results

Q-PCR showed that miR-214 and Dnm3os expression was upregulated in mouse and human ADPKD kidneys. In situ hybridization revealed that miR-214 and Dnm3os are expressed in both the cyst epithelium and interstitium. miR-214^-/- mice displayed no phenotypic abnormalities. Deletion of miR-214 in Pkd2-KO mice increased kidney weight/body weight ratio, raised serum BUN and shortened survival. Pathway analysis of differentially expressed genes revealed that miR-214 deletion results in a shift in the type of inflammation present in Pkd2-KO kidneys. Accordingly, further molecular and histological analysis revealed an increase in M2-like macrophages in Pkd2-miR-214-KO kidneys. Conversely, miR-214 mimics reduced expression of M2 markers and cytokines in RAW264.7 and mIMCD3 cells. Deleting miR-214 in a second long-lived, slowly-progressing mouse model, the Pkd1^RC/RC mouse, also led to increased total kidney volumes as measured by serial MRI and an increase in M2-like macrophages.

Conclusion

miR-214 expression is increased in mouse and human ADPKD kidneys. Deletion of miR-214 aggravates cyst growth and shortens survival. miR-214 may suppress cyst growth by inhibiting M2-like polarization of macrophages. Our studies suggest that augmenting miR-214 may be a potential novel therapeutic approach for ADPKD.

Funding

• NIDDK Support