Study On The Regulation Of MicroRNA-25 In Diabetic Nephropathy And Heart Failure

MicroRNA is a kind of endogenous,non-coding single-stranded small RNA discovered in recent years,which plays an important role in the development and differentiation of organisms,organ formation,cell proliferation,apoptosis and even the occurrence of diseases,and has become a hot research topic in recent years.Each miRNA has the potential to regulate the expression of several or even hundreds of target genes,so the entire miRNA pathway may play a key role in gene expression and control.Numerous studies have demonstrated that miRNAs may be necessary to maintain tissue differentiation,since the expression of many tissue-specific miRNAs varies in many diseases,including cancer.There are certain changes in the expression profile of miRNA in different diseases or different stages of the same disease,which provide great potential for clinical diagnosis based on the characteristics of miRNA.With the deepening of research on miRNA,more and more human diseases are closely related to miRNA,and efforts are being made to develop therapeutic drugs directly targeting miRNA.Diabetic nephropathy is characterized by persistent albuminuria,progressive decline in GFR,and secondary hypertension.MicroRNAs are dysregulated in diabetic nephropathy,but identification of the specific microRNAs involved remains incomplete.Here,we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25(miR-25)compared with those of their nondiabetic counterparts.Furthermore,treatment with high glucose decreased the expression of miR-25 in cultured kidney cells.In db/db mice,systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP.Notably,knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria,extracellular matrix accumulation,podocyte foot process effacement,and hypertension with renin-angiotensin system activation.However,excessive miR-25 did not cause kidney dysfunction in wild-type mice.RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice,including the Ras-related gene CDC42.In vitro,cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 3? untranslated region.In conclusion,these results reveal a role for miR-25 in diabetic nephropathy and indicate a potential novel therapeutic target for this disease.Heart failure is one of the leading causes of death in the global population.Heart failure arises from diverse cardiovascular diseases,including hypertension,ischemic disease and atherosclerosis,valvular insufficiency,myocarditis,and contractile protein mutations.Among these different causes,long-term stress stimulation affects ventricular remodeling processes,involving multiple molecular and cellular events,such as genetic changes,hypertrophic growth,fibrosis,apoptosis,and endothelial dysfunction,resulting in structural changes in the heart and impaired systolic function.MicroRNAs are dysregulated in heart failure,but identification of the specific microRNAs involved remains incomplete.Here,we evaluate miR-25 expression in the peripheral blood from healthy,dilated cardiomyopathy(DCM),remote infarct(OMI),hypertensive heart disease(HHD),and HHD resulting in heart failure(HHDF)using q-PCR.Interestingly,we discovered miR-25 expression in humans is initially decreased at the onset of heart failure but is later increased in end-stage heart failure.We also show that overexpression of miR-25 in normal mice causes cardiomyocyte fibrosis and apoptosis.However,inhibition of miR-25 in normal mice led to activate renin-angiotensin system(RAS)and high blood pressure,mild heart dilation.Notably,the miR-25 cluster knock-out mice was also characterized high blood pressure and no obvious cardiac function alteration.RNA sequencing showed the alteration of miR-25 target genes in angomir-treated mice,including the renin secretion signal related gene.In vitro,cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the Pde3 a and Cacnalc untranslated region.In summary,miR-25 expression during different stages of heart disease,offers a new perspective for the role of miR-25 function in heart failure.