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Role of kidney function on Nrf2 mRNA levels in type 2 diabetes
Belinda Spoto1, Cristina Politi2, Maurizio Postorino3
1Institute of Clinical Physiology Reggio Calabria Branch National Research Council, Reggio Calabria, Italy belinda.spoto@tin.it.
Introduction:
Diabetic kidney disease (DKD) is a major complication in patients with diabetes and the main contributor to the chronic kidney disease (CKD) global burden. Oxidative stress is a crucial factor in DKD pathogenesis but the role of the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) and its molecular regulators has been poorly investigated in man.
Research Design And Methods:
In this case-control study, we analyzed the roles of Nrf2, a transcription factor shielding cells from oxidative stress, its repressor Kelch-like ECH-associated protein 1 (Keap1) and six microRNAs (miRNAs) that potentially suppress Nrf2. We categorized 99 participants into 3 groups: 33 non-dialysis patients with type 2 diabetes with DKD, 33 patients with type 2 diabetes without DKD and 33 control subjects and quantified the gene expression (messenger RNA (mRNA)) levels of Nrf2, Keap1 and 6 miRNAs. Moreover, we studied the correlation between gene expression levels and clinical indicators of kidney health.
Results:
In patients with diabetes with DKD, Nrf2 mRNA levels were significantly lower than in patients without DKD (p=0.01) and controls (p=0.02), whereas no difference in Nrf2 expression levels existed between patients without DKD and controls. Conversely, in patients with and without DKD, Keap1 expression levels were significantly higher than in controls. Of the six miRNAs studied, miRNA 30e-5p showed differential expression, being markedly reduced in patients with DKD (p=0.007). Nrf2 mRNA levels directly correlated with estimated glomerular filtration rate (eGFR) in patients with DKD (r=0.34, p=0.05) and in a formal mediation analysis the eGFR emerged as the first factor in rank for explaining the difference in Nrf2 mRNA levels between patients with and without DKD.
Conclusions:
The observed dysregulation in the Nrf2-Keap1 axis and the unique expression pattern of miRNA30e-5p in DKD underscore the need for more focused research in this domain that can help identify novel intervention strategies for DKD in patients with type 2 diabetes.
Insights
Diabetic kidney disease (DKD) involves lower Nrf2 antioxidant levels and higher Keap1 repressor levels. MicroRNA 30e-5p is also reduced in DKD, impacting kidney function.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) globally.
- Oxidative stress is implicated in DKD pathogenesis.
- The role of the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) and its regulators in human DKD is under-investigated.
Purpose of the Study:
- To investigate the roles of Nrf2, its repressor Keap1, and specific microRNAs (miRNAs) in patients with type 2 diabetes and DKD.
- To analyze gene expression levels and their correlation with kidney health indicators.
Main Methods:
- Case-control study involving 99 participants: 33 with DKD, 33 with type 2 diabetes without DKD, and 33 controls.
- Quantification of messenger RNA (mRNA) levels for Nrf2, Keap1, and six miRNAs.
- Correlation analysis between gene expression and clinical kidney health indicators, including estimated glomerular filtration rate (eGFR).
Main Results:
- Nrf2 mRNA levels were significantly lower in patients with DKD compared to those without DKD and controls.
- Keap1 expression levels were significantly higher in patients with and without DKD compared to controls.
- MicroRNA 30e-5p was markedly reduced in patients with DKD. Nrf2 mRNA levels directly correlated with eGFR in DKD patients.
Conclusions:
- Dysregulation of the Nrf2-Keap1 axis and altered miRNA30e-5p expression are observed in DKD.
- These findings highlight the need for further research into novel intervention strategies for DKD in type 2 diabetes patients.
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