Suppression of Foxo3-Gatm by miR-132-3p Accelerates Cyst Formation by Up-Regulating ROS in Autosomal Dominant Polycystic Kidney Disease
| Autor: | Do Yeon Kim, Jong Hoon Park, Seonju Choi, Eun Ji Lee, Yejin Ahn |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Autosomal dominant polycystic kidney disease Biology urologic and male genital diseases medicine.disease_cause Biochemistry 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Drug Discovery Conditional gene knockout medicine Cystogenesis ADPKD Pharmacology Gene knockdown PKD1 urogenital system Microarray analysis techniques FOXO3 ROS MicroRNA medicine.disease female genital diseases and pregnancy complications Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine Original Article Oxidative stress |
| Zdroj: | Biomolecules & Therapeutics |
| ISSN: | 2005-4483 1976-9148 |
| Popis: | Accumulation of reactive oxygen species (ROS) is associated with the development of various diseases. However, the molecular mechanisms underlying oxidative stress that lead to such diseases like autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Here, we observed that oxidative stress markers were increased in Pkd1f/f:HoxB7-Cre mice. Forkhead transcription factors of the O class (FOXOs) are known key regulators of the oxidative stress response, which have been observed with the expression of FoxO3a in an ADPKD mouse model in the present study. An integrated analysis of two datasets for differentially expressed miRNA, such as miRNA sequencing analysis of Pkd1 conditional knockout mice and microarray analysis of samples from ADPKD patients, showed that miR-132-3p was a key regulator of FOXO3a in ADPKD. miR-132-3p was significantly upregulated in ADPKD which directly targeted FOXO3 in both mouse and human cell lines. Interestingly, the mitochondrial gene Gatm was downregulated in ADPKD which led to a decreased inhibition of Foxo3. Overexpression of miR-132-3p coupled with knockdown of Foxo3 and Gatm increased ROS and accelerated cyst formation in 3D culture. This study reveals a novel mechanism involving miR-132-3p, Foxo3, and Gatm that is associated with the oxidative stress that occurs during cystogenesis in ADPKD. |
| Databáze: | OpenAIRE |
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