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Published on: September 1, 2015
MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease
Ronak Lakhia1, Sachin Hajarnis1, Darren Williams1
1Department of Internal Medicine and.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4 Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.
Insights
MicroRNA-21 (miR-21) drives polycystic kidney disease (PKD) progression by inhibiting cell apoptosis. Inhibiting miR-21 may offer a new therapeutic strategy for PKD.
Area of Science:
- Molecular Biology
- Genetics
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to kidney failure via cyst growth.
- The role of microRNAs (miRs) in ADPKD pathogenesis remains unclear.
- miR-21 is an oncogenic microRNA implicated in various diseases.
Purpose of the Study:
- To investigate the role of miR-21 in kidney cyst growth in ADPKD.
- To explore the regulatory mechanisms of miR-21 expression in PKD.
- To evaluate the therapeutic potential of targeting miR-21 in experimental PKD.
Main Methods:
- Analysis of miR-21 levels in murine and human ADPKD kidney samples.
- Investigating the effect of cAMP signaling on miR-21 promoter activity.
- Utilizing a genetic deletion model of miR-21 in an orthologous ADPKD model.
- RNA sequencing and in vivo assays to identify miR-21 targets and functions.
Main Results:
- miR-21 expression is upregulated in murine PKD and human ADPKD cysts.
- cAMP signaling activates miR-21 expression in kidney cells and cystic kidneys.
- Genetic deletion of miR-21 reduced cyst burden, kidney injury, and improved survival in an ADPKD model.
- miR-21 was found to inhibit apoptosis of cyst epithelial cells by repressing programmed cell death 4.
Conclusions:
- miR-21 promotes PKD progression downstream of cAMP signaling.
- Inhibiting miR-21 represents a potential therapeutic strategy to slow cyst growth in ADPKD.
- Targeting miR-21 may offer a novel approach for treating polycystic kidney disease.
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