Interactions Among RNAs In Type ? Cardiorenal Syndrome Induced By Right Ventricular Dysfunction

BackgroundCardiorenal syndrome refers to the disease of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other.Cardiorenal syndrome is divided into five types based on the initial damaged organ and the severity of the injury,of which type ? is defined as chronic heart dysfunction induced chronic kidney dysfunction.With the progress of heart failure,the disease can further lead to diuretic resistance and worsening renal function.Researchers are used to owe the cause of type ? cardiorenal syndrome to left heart failure.Is the right ventricular dysfunction caused by pulmonary artery hypertension also able to induce renal dysfunction to produce type ? cardiorenal syndrome?If so,what are the potiential molecular mechanisms?Pulmonary artery hypertension can cause right ventricular dysfunction andright heart failure,and is an independent risk factor for the mortality of end-stage renal disease.Mice with increased pulmonary vascular resistance and elevated right ventricular pressure will have secondary manifestations of renal dysfunction such as water retention and systemic edema.Clinically,patients with pulmonary artery hypertension also develop peripheral edema and ascites.As the pulmonary hypertension progresses,resistance to diuretics often occurs.The combined damage of the kidney and the heart not only misleading the diagnosis and identification of the worsening heart function,but also makes it harder to choose the appropriate treatments.Until now,the main purpose of treatment of type ? cardiorenal symdrome is still the relief of symptoms.Therefore,it is necessary to find new therapeutic targets to more effectively treat type ? cardiorenal syndrome caused by right ventricular dysfunction.Non-coding RNAs have been reported to have transcriptional and post-transcriptional regulatory functions and are able to regulate downstream gene expression.MicroRNAs(miRNA)and circular RNAs(circRNA)are considered to be closely related to the development of cardiovascular or kidney diseases.CircRNAs can also function as the competitive endogenous RNA(ceRNA)of miRNAs,which can regulate downstream messenger RNAs(mRNA),thereby regulating the pathophysiology of cardiorenal syndrome.This study aims to investigate the transcriptome expression profile of circRNA,miRNA and mRNA in type ? cardiorenal syndrome,and to identify potential therapeutic targets for regulating molecular signaling networks in right ventricular dysfunction-induced type ? cardiorenal syndrome.MethodsMale C57BL/6 mice receiving pulmonary artery constriction were used to establish right ventricular dysfunction model.Echocardiographic examination,hemodynamic test and histological staining were used to verify the success of the animal model.The expression profiles of mRNAs,miRNAs and circRNAs in right ventricular and kidney tissues were obtained by whole transcriptome sequencing.Bioinformatics analyses were performed,including Gene Ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis and co-expression network analysis.Real-time quantitative polymerase chain reaction(qRT-PCR)was used to confirm the results of transcriptome sequencing.FindingsPulmonary arterial constricted mice developed severe right ventricular dysfunction,including right ventricular hypertrophy and fibrosis.Renal atrophy and dysfunction with elevated creatinine were observed subsequently.Through whole transcriptome sequencing,a total of 741 and 86 differentially expressed mRNAs,159 and 29 differentially expressed miRNAs and 233 and 104 differentially expressed circRNAs were found in right ventricular and kidney tissue,respectively.Pairs of miRNA-mRNA were established.GO and KEGG analysis displayed a significant correlation with proliferative,fibrotic signaling pathways and metabolic pathways.Then the circRNA-miRNA-mRNA network related to proliferation,fibrosis and metabolic pathways were established.The network revealed ceRNA pairs such as novel_circ₀02631/miR-181a-5p/Greb1 play an important role in fibrosis through Ras,cGMP-PKG or PI3K-Akt pathways,and ceRNA pairs such as novel_circ₀05533/miR-133a-3p/Hdac4 may play an important role in the metabolic switches through thyroid and sphingolipid metabolic pathways.InterpretationThese findings indicated that the significantly dysregulated RNAs of ceRNA network are mainly involved in the proliferation and fibrosis progresses through Ras,PI3K/Akt or cGMP-PKG pathways,and in the metabolic transformation through thyroid or sphingolipid metabolic pathways in right ventricular dysfunction induced type ? cardiorenal syndrome.Therefore,these circRNA-miRNA-mRNA pairs should be potential targets for treatment of this disease.