Analysis Of MicroRNA Expression After Glutamine Intervention in Acute Renal Ischemia-Reperfusion Injury

4. Discussion 

It's of great clinical value to avoid or reduce renal ischemia-reperfusion injury. GLN has antioxidant and anti-inflammatory effects and can protect the kidney from the severe consequences of ischemia-reperfusion injury [15]. In this study, we found that treatment with GLN significantly decreased SCr and BUN levels and attenuated tubular injury. These effects contributed to its protective effects against I/R-induced AKI. Most importantly, we revealed a novel mechanism of GLN function that was involved in the cGMP-PKG signaling pathway by downregulating miR-132-5p.

miRNAs usually act by binding to the 3′ untranslated regions of target mRNAs, which leads to mRNA degradation and prevents protein translation [16, 17]. In related studies, miRNAs have been found to contribute to the therapeutic target of AKI and kidney repair by regulating inflammation, apoptosis, proliferation, and angiogenesis [18, 19]. Studies on the protective effect of glutamine on the kidney have been carried out in recent years, but there are few studies on the mechanism of glutamine-mediated protection of the kidney at the miRNA level.

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A total of 104 miRNAs with significant differential expression were screened from the I/R group and I/R + GLN group. Among the key miRNAs we identified, miR-132 plays a great immunoregulatory role in immunity, with CD4 + T cells expressing higher levels of miR-132 and T-cell activation leading to upregulation of miR-132 [20]. miR- 132-5p was upregulated in the I/R + GLN group, suggesting that Gln treatment might improve CD4 + T-cell immune activity. miR-205 was significantly down-expressed in AKI patients and was found to be negatively correlated with SCr and BUN and was an independent risk factor for the prognosis of AKI patients [21]. 

miR-205 is considered a target for the treatment of oxidative stress- and autophagy-related pathological processes during AKI [22, 23]. +is implies that GLN may utilize miR-205 to regulate oxidative damage in AKI. miR-615 is downregulated in renal transplantation and focal segmental glomerulosclerosis [24, 25]. However, no studies have been found to show the relationship between miR-615 and I/R. 

Figure 4: +e expression of key miRNAs in the sham group, I/R group, and I/R + GLN group detected by qRT-PCR. ∗P < 0.05 and ∗∗P < 0.01.

Figure 5: +e enrichment analysis of target genes. (a) +e top 10 GO terms of target genes enrichment. Red refers to biological processes, blue refers to cell composition, and green refers to molecular function. (b) +e KEGG pathways of target genes enriched.

We further investigated the downstream target regulatory mechanism underlying the altered expression of miRNAs by GLN treatment I/R. In the KEGG pathways, Notch signaling activation plays a promoting role in I/R-associated inflammation and apoptosis [26]. Inhibition of Notch signaling may be a potential anti-inflammatory strategy for the treatment of kidney disease [27]. Activation of the PI3K-Akt signal pathway may play positive roles in antiapoptosis and protecting the kidney from I/R injury [28, 29]. In recent years, the activation of the cGMP/PKG pathway as a therapeutic method to reduce I/R injury has attracted extensive attention, and one of its important protective mechanisms is to participate in the antiapoptotic process [30–32]. These results indicated that GLN may reduce the degree of I/R-induced AKI through the cGMPPKG pathway.

Some limitations of our study should be taken into account. First, we did not perform high-throughput sequencing of miRNA expression in the sham group, which may affect the identification of genes involved in GLN treatment. In the cellular model, we did not perform the treatment of GLN to verify the alteration of signaling pathways brought about by its treatment. Future studies will be required to prospectively evaluate key miRNAs as molecular regulatory mechanisms for GLN treatment.

5. Conclusions 

In conclusion, using the high-throughput sequencing technique, this experiment found that, after glutamine intervention, there was a significant differential expression of miRNA in renal histocytes with ischemia-reperfusion injury in vitro, which may be related to the upregulated key miRNAs. +e cGMP-PKG pathway influenced by miR-132- 5p may be involved in the treatment of I/R by GLN. However, further study is needed to clarify the specific regulatory mechanism.

References 

[1] C. Vazquez-Carballo, M. Guerrero-Hue, C. Garcia-Caballero et al., "Toll-like receptors in acute kidney injury," International Journal of Molecular Sciences, vol. 22, 2021. 

[2] Y. L. Wu, H. F. Li, H. H. Chen, and H. Lin, "MicroRNAs as biomarkers and therapeutic targets in inflammation- and ischemia-reperfusion-related acute renal Injury," International Journal of Molecular Sciences, vol. 21, 2020. 

[3] A. A. Sharfuddin and B. A. Molitoris, "Pathophysiology of ischemic acute kidney injury," Nature Reviews Nephrology, vol. 7, no. 4, pp. 189–200, 2011. [4] Y. Yan, Z. Ma, J. Zhu, M. Zeng, H. Liu, and Z. Dong, "miR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury," American Journal of Physiology-Renal Physiology, vol. 318, no. 4, pp. F878–F887, 2020. 

[5] Y. Yang, M. Song, Y. Liu et al., "Renoprotective approaches and strategies in acute kidney injury," Pharmacology and therapeutics, vol. 163, pp. 58–73, 2016. 

[6] B. A. Molitoris, "+erapeutic translation in acute kidney injury: the epithelial/endothelial axis," Journal of Clinical Investigation, vol. 124, no. 6, pp. 2355–2363, 2014. 

[7] N. Petejova, A. Martinek, J. Zadrazil et al., "Acute kidney injury in septic patients treated by selected nephrotoxic antibiotic agents-pathophysiology and biomarkers-a review," International Journal of Molecular Sciences, vol. 21, 2020. 

[8] H.-J. Kim, D. J. Park, J. H. Kim et al., "Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation," Journal of Pharmacological Sciences, vol. 127, no. 1, pp. 117–126, 2015. 

[9] F. Zhan, X. Wang, J. Zhang, S. Yi, and P. He, "Glutamine alleviates the renal dysfunction associated with gentamicin-induced acute kidney injury in Sprague-Dawley rats," Biotechnology and Applied Biochemistry, 2021. 

[10] K. C. Liboni, N. Li, P. O. Scumpia, and J. Neu, "Glutamine modulates LPS-induced IL-8 production through IκB/NF-κB in human fetal and adult intestinal epithelium," Journal of Nutrition, vol. 135, no. 2, pp. 245–251, 2005.

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