How Important Is MiRNA-125b-5p And MiRNA-181b-5 in Diagnosis And Treatment Of Diabetic Kidney Disease
Mar 26, 2022
Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791
HIROKIISHII,SHOHEI KANEKO,KATSUNORI YANAl,AKINORI AOMATSU,KEIJ HIRAl, SUSUMU OOKAWARA, & YOSHIYUKI MORISHITA
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DISCUSSION
In the present study, miRNA-125b-5p and miRNA-181b-5p were found to be useful diagnostic biomarkers of DKD(Diabetic Kidney Disease). Additionally, the overexpression of miRNA-181b-5p in the kidney may represent a therapeutic target for DKD(Diabetic Kidney Disease).
Previous studies have shown that the expression of however, many miRNAsis altered in the DKD(Diabetic Kidney Disease);16,29,30 however, the roles of miRNA-125b-5p and miRNA-181b-5p in DKD(Diabetic Kidney Disease) have not previously been reported. This may be because of differences in experimental methods and the clinical setting. In the present study, we first screened miRNAs for differential expression in two mouse models of DKD(Diabetic Kidney Disease), to reduce the influence of mouse strain and the type of diabetes mellitus. We were able to show that six miRNAs (miRNA-34a-5p, miRNA-129b-1-3p,miRNA-125b-5p,miRNA-142a-3p,miRNA-181b-5p,and miRNA-223-3p)were differentially expressed in the kidneys of both models of DKD(Diabetic Kidney Disease).Of these,miRNA-125b-5p and miRNA-181b-5p were selected as candidate therapeutic targets for and biomarkers of DKD(Diabetic Kidney Disease) because their expression levels were not affected by other renal diseases in mice(renal fibrosis, acute kidney injury, aging-related renal dis-ease, and immunoglobulin A nephropathy): the expression levels of miRNA-125b-5p and miRNA-181b-5p and were specifically upregulated in DKD(Diabetic Kidney Disease).
Although the expression of miRNA-181b-5p was not detected by ISH, miRNA-125b-5p was detected and the positive(U6)and negative controls(scrambled probe)also worked. Therefore, the expression levels of miRNA-181b-5p might have been below the detection level of ISH. However, technical problems including the probe, incubation time, and other experimental conditions cannot be ruled out. Further study to investigate the localization of miRNA-181b-5p in kidneys is necessary.
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In AKITA mice,miRNA-125b-5p was decreased in the kidneys but increased in the serum. In DKD(Diabetic Kidney Disease), inconsistent changes in the expression of miRNAs between kidneys and serum or urine have been reported.29 For example, miRNA-30c was decreased in the kidneys of DKD(Diabetic Kidney Disease) patients but increased in their serum.313In other diseases (renal cell carcinoma), miRNA-21 was 31,32 decreased in renal tissues but increased in serum.33,34 These discrepancies regarding the expression levels of miRNA between organs, blood, and urine in specific diseases might be explained by extracellular miRNAs, which are released into the blood as mediators of Several miRNAs intercellular communications.35
exported by one cell and recognized, taken up,and utilized by other cells might result in decreased or increased expression levels of miRNAs in blood and urine which differ from those in diseased organs.35 Further studies to investigate the function and circula-tion of miRNAs in DKD(Diabetic Kidney Disease) in vivo are necessary.
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The potential utility of the serum concentrations of miRNA-125b-5p and miRNA-181b-5p as biomarkers of DKD(Diabetic Kidney Disease) was also investigated in patients with DKD(Diabetic Kidney Disease) and other kidney diseases. All the participants had renal diseases that were histologically diagnosed following renal biopsy, using light microscopy, immunofluorescence, and electron microscopy that was performed by experienced pathologists, which should have increased the robustness of the results. We showed that the serum levels of miRNA-125b-5p and miRNA-181b-5p significantly discriminated patients with DKD(Diabetic Kidney Disease) from those with kidney diseases other than DKD(Diabetic Kidney Disease) using ROC analysis (miRNA-125b-5p:AUC 0.74,P<0.05,miRNA-181b-5p: AUC0.76,P<0.05). Furthermore, the ratio of the serum levels of miRNA-125b-5p and miRNA-181b-5p (miRNA-125b-5p/miRNA-181b-5p) increased the diagnostic utility for differentiating DKD(Diabetic Kidney Disease) from other kidney diseases(ROC analysis: AUC0.84,P<0.05),and it was also capable of discriminating patients with DKD(Diabetic Kidney Disease) from those with kidney diseases other than DKD(Diabetic Kidney Disease) that were complicated by diabetes mellitus (ROC analysis: AUC 0.86, P<0.01). These findings suggest that the serum levels of miRNA-125b-5p and miRNA-181b-5p and their ratio may represent useful diagnostic biomarkers of DKD(Diabetic Kidney Disease).
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To investigate the therapeutic effects of miRNAs, artificially synthesized miRNA-125b-5p and miRNA-181b-5p carried by PEI-NPs were overexpressed in the kidneys. PEI-NPs are polymers that have been reported to effectively deliver oligonucleotides that modulate target gene expression in the kidney, as well as being considered preferable to viral vectors, because of their long-term safety and biocompatibility.27 Overexpression of miRNA-181b-5p ameliorated the abnormal glomerular enlargement, mesangial expansion, and tubulointerstitial fibrosis in db/db mice, which was associated with differential expression of a number of and 29 were (24 were upregulated genes (downregulated by more than fourfold vs. normal mice) in the kidneys of db/db mice. In contrast, the administration of control miRNAs resulted in the upregulation of one gene and the downregulation of one gene by more than four-fold. Furthermore, signaling pathway analysis using microarrays followed by qRT-PCR showed miRNA-181b-5p-mimic-PEI-NP administration changed the expression of seven mRNAs (Slc25a25, Gli3, Cryl,Erc2, Nrld1, Creb3l3, Psme3)in six signaling pathways in db/db mice. These results suggest that miRNA-181b-5p influences DKD(Diabetic Kidney Disease) by modulating various signaling pathways. Of these genes, Cryl has been reported to influence DKD(Diabetic Kidney Disease) by disrupting the circadian rhythm, which results in cellular instability.36.37 The other mRNAs have not been reported to be associated with the development of DKD(Diabetic Kidney Disease), but the roles of these mRNAs should be investigated in future studies. In contrast, overexpression of mi-125b-5pRNA did not have any effects on DKD(Diabetic Kidney Disease) in vivo.
The present study had several limitations. The analysis of the findings may have been limited by the sample size. Second, the effects of miRNA-181b-5p-mimic-PEI-NPs in other organs should also be investigated in future studies.
In conclusion,miRNA-125b-5p and miRNA-181b-5p may represent useful novel diagnostic biomarkers and miRNA-181b-5p may represent a therapeutic target for DKD(Diabetic Kidney Disease).
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Abbreviations: BMI= body mass index; DAPI=4,6-diamidino-2-phenylindole; FITC= fluorescein isothiocyanate; DKD= diabetic kidney disease; eGFR= estimated glomerular fltration rate;HDL high-density lipoprotein; HIGA= high immunoglobulin A; IRI= ischemia-reperfusion injury;LDL= low-density lipoprotein; ns= not significant; PEI-NPs= polyethylenimine nanoparticles;RNU6=U6 Small Nuclear 1; SAMP=senescence-accelerated mouse; SAMR=control for the senescence accelerated mouse; UACR= urine albumin-to-creatinine ratio; UUO = unilateral ureteral obstruction
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