Dataset Information

MiR-802-5p is a key regulator in diabetic kidney disease.

ABSTRACT:

Background

Diabetic kidney disease has substantial burden and limited therapeutic options. An inadequate understanding of the complex gene regulatory circuits underlying this disorder contributes to the insufficiency of current treatment strategies. MicroRNAs (miRNAs) play a crucial role as regulators of functionally related gene networks. Previously, mmu-mir-802-5p was identified as the sole dysregulated miRNA in both the kidney cortex and medulla of diabetic mice. This study aims to investigate the role of miR-802-5p in diabetic kidney disease.

Materials and methods

The validated and predicted targets of miR-802-5p were identified using miRTarBase and TargetScan databases, respectively. The functional role of this miRNA was inferred using gene ontology enrichment analysis. The expression of miR-802-5p and its selected targets were assessed by qPCR. The expression of the angiotensin receptor (Agtr1a) was measured by ELISA.

Results

miR-802-5p exhibited dysregulation in both the kidney cortex and medulla of diabetic mice, with two- and four-fold over-expressions, respectively. Functional enrichment analysis of the validated and predicted targets of miR-802-5p revealed its involvement in the renin-angiotensin pathway, inflammation, and kidney development. Differential expression was observed in the Pten transcript and Agtr1a protein among the examined gene targets.

Conclusion

These findings suggest that miR-802-5p is a critical regulator of diabetic nephropathy in the cortex and medulla compartments, contributing to disease pathogenesis through the renin-angiotensin axis and inflammatory pathways.

SUBMITTER: Kiyanpour F

PROVIDER: S-EPMC10315408 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-802-5p is a key regulator in diabetic kidney disease.

Kiyanpour Farnoush F Abedi Maryam M Gheisari Yousof Y

Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences 20230529

<h4>Background</h4>Diabetic kidney disease has substantial burden and limited therapeutic options. An inadequate understanding of the complex gene regulatory circuits underlying this disorder contributes to the insufficiency of current treatment strategies. MicroRNAs (miRNAs) play a crucial role as regulators of functionally related gene networks. Previously, mmu-mir-802-5p was identified as the sole dysregulated miRNA in both the kidney cortex and medulla of diabetic mice. This study aims to in ...[more]

PMID: 37405075

Similar Datasets

Project description:Breast cancer brain metastases (BCBMs) have been underinvestigated despite their high incidence and poor outcome. MicroRNAs (miRNAs), and particularly circulating miRNAs, regulate multiple cellular functions, and their deregulation has been reported in different types of cancer and metastasis. However, their signature in plasma along brain metastasis development and their relevant targets remain undetermined. Here, we used a mouse model of BCBM and next-generation sequencing (NGS) to establish the alterations in circulating miRNAs during brain metastasis formation and development. We further performed bioinformatics analysis to identify their targets with relevance in the metastatic process. We additionally analyzed human resected brain metastasis samples of breast cancer patients for target expression validation. Breast cancer cells were injected in the carotid artery of mice to preferentially induce metastasis in the brain, and samples were collected at different timepoints (5 h, 3, 7, and 10 days) to follow metastasis development in the brain and in peripheral organs. Metastases were detected from 7 days onwards, mainly in the brain. NGS revealed a deregulation of circulating miRNA profile during BCBM progression, rising from 18% at 3 days to 30% at 10 days following malignant cells' injection. Work was focused on those altered prior to metastasis detection, among which were miR-802-5p and miR-194-5p, whose downregulation was validated by qPCR. Using targetscan and diana tools, the transcription factor myocyte enhancer factor 2C (MEF2C) was identified as a target for both miRNAs, and its expression was increasingly observed in malignant cells along brain metastasis development. Its upregulation was also observed in peritumoral astrocytes pointing to a role of MEF2C in the crosstalk between tumor cells and astrocytes. MEF2C expression was also observed in human BCBM, validating the observation in mouse. Collectively, downregulation of circulating miR-802-5p and miR-194-5p appears as a precocious event in BCBM and MEF2C emerges as a new player in brain metastasis development.

Project description:Emerging evidence suggests that GSK3β, a redox-sensitive transducer downstream of insulin signaling, acts as a convergent point for myriad pathways implicated in kidney injury, repair, and regeneration. However, its role in diabetic kidney disease remains controversial. In cultured glomerular podocytes, exposure to a milieu of type 2 diabetes elicited prominent signs of podocyte injury and degeneration, marked by loss of homeostatic marker proteins like synaptopodin, actin cytoskeleton disruption, oxidative stress, apoptosis, and stress-induced premature senescence, as shown by increased staining for senescence-associated β-galactosidase activity, amplified formation of γH2AX foci, and elevated expression of mediators of senescence signaling, like p21 and p16INK4A. These degenerative changes coincided with GSK3β hyperactivity, as evidenced by GSK3β overexpression and reduced inhibitory phosphorylation of GSK3β, and were averted by tideglusib, a highly-selective small molecule inhibitor of GSK3β. In agreement, post-hoc analysis of a publicly-available glomerular transcriptomics dataset from patients with type 2 diabetic nephropathy revealed that the curated diabetic nephropathy-related gene set was enriched in high GSK3β expression group. Mechanistically, GSK3β-modulated nuclear factor Nrf2 signaling is involved in diabetic podocytopathy, because GSK3β knockdown reinforced Nrf2 antioxidant response and suppressed oxidative stress, resulting in an improvement in podocyte injury and senescence. Conversely, ectopic expression of the constitutively active mutant of GSK3β impaired Nrf2 antioxidant response and augmented oxidative stress, culminating in an exacerbated diabetic podocyte injury and senescence. Moreover, IRS-1 was found to be a cognate substrate of GSK3β for phosphorylation at IRS-1S332, which negatively regulates IRS-1 activity. GSK3β hyperactivity promoted IRS-1 phosphorylation, denoting a desensitized insulin signaling. Consistently, in vivo in db/db mice with diabetic nephropathy, GSK3β was hyperactive in glomerular podocytes, associated with IRS-1 hyperphosphorylation, impaired Nrf2 response and premature senescence. Our finding suggests that GSK3β is likely a novel therapeutic target for treating type 2 diabetic glomerular injury.