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Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring
Published on: June 23, 2015
Parallel analysis of mRNA and microRNA microarray profiles to explore functional regulatory patterns in polycystic
Harsh Dweep1, Carsten Sticht, Asawari Kharkar
1Medical Faculty Mannheim, Medical Research Center, University of Heidelberg, Mannheim, Germany.
Abstract:
Autosomal polycystic kidney disease (ADPKD) is a frequent monogenic renal disease, characterised by fluid-filled cysts that are thought to result from multiple deregulated pathways such as cell proliferation and apoptosis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of many genes associated with such biological processes and human pathologies. To explore the possible regulatory role of miRNAs in PKD, the PKD/Mhm (cy/+) rat, served as a model to study human ADPKD. A parallel microarray-based approach was conducted to profile the expression changes of mRNAs and miRNAs in PKD/Mhm rats. 1,573 up- and 1,760 down-regulated genes were differentially expressed in PKD/Mhm. These genes are associated with 17 pathways (such as focal adhesion, cell cycle, ECM-receptor interaction, DNA replication and metabolic pathways) and 47 (e.g., cell proliferation, Wnt and Tgfβ signaling) Gene Ontologies. Furthermore, we found the similar expression patterns of deregulated genes between PKD/Mhm (cy/+) rat and human ADPKD, PKD1(L3/L3), PKD1(-/-), Hnf1α-deficient, and Glis2(lacZ/lacZ) models. Additionally, several differentially regulated genes were noted to be target hubs for miRNAs. We also obtained 8 significantly up-regulated miRNAs (rno-miR-199a-5p, -214, -146b, -21, -34a, -132, -31 and -503) in diseased kidneys of PKD/Mhm rats. Additionally, the binding site overrepresentation and pathway enrichment analyses were accomplished on the putative targets of these 8 miRNAs. 7 out of these 8 miRNAs and their possible interactions have not been previously described in ADPKD. We have shown a strong overlap of functional patterns (pathways) between deregulated miRNAs and mRNAs in the PKD/Mhm (cy/+) rat model. Our findings suggest that several miRNAs may be associated in regulating pathways in ADPKD. We further describe novel miRNAs and their possible targets in ADPKD, which will open new avenues to understand the pathogenesis of human ADPKD. Furthermore they could serve as a useful resource for anti-fibrotic therapeutics.
Insights
This study identifies novel microRNAs (miRNAs) and their targets involved in regulating pathways in autosomal polycystic kidney disease (ADPKD). These findings offer new insights into ADPKD pathogenesis and potential anti-fibrotic therapeutic strategies.
Area of Science:
- Genetics and Molecular Biology
- Renal Pathophysiology
- Biochemistry
Background:
- Autosomal polycystic kidney disease (ADPKD) is a common inherited kidney disorder characterized by cyst formation.
- MicroRNAs (miRNAs) are key regulators of gene expression implicated in various diseases, including ADPKD.
- Understanding miRNA roles in ADPKD is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the regulatory role of miRNAs in ADPKD using a rat model.
- To identify differentially expressed miRNAs and their potential mRNA targets in ADPKD kidneys.
- To explore novel miRNA-mRNA interactions in ADPKD pathogenesis.
Main Methods:
- Utilized a PKD/Mhm (cy/+) rat model mirroring human ADPKD.
- Performed parallel microarray analysis to profile mRNA and miRNA expression.
- Conducted bioinformatic analyses including pathway enrichment and target prediction for identified miRNAs.
Main Results:
- Identified 1,573 up-regulated and 1,760 down-regulated genes in PKD/Mhm rats, associated with key pathways like cell proliferation and Wnt signaling.
- Found similar gene expression patterns between the rat model and various human ADPKD models.
- Discovered 8 significantly up-regulated miRNAs in diseased kidneys, with 7 showing previously undescribed roles in ADPKD.
Conclusions:
- Multiple miRNAs are likely involved in regulating ADPKD-associated pathways.
- Novel miRNAs and their targets identified in this study provide new avenues for understanding ADPKD pathogenesis.
- These findings may serve as a basis for developing novel anti-fibrotic therapeutics for ADPKD.
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