Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Alteration in microRNA-25 Balance Causes Heart and Kidney Impairment

ABSTRACT: Contradictorily, both up- and downregulation of miR-25 can reverse heart failure. Importantly, these findings were based on the same animal model of pressure overloaded transverse aortic constriction (TAC) mice. How can we explain and, if possible, reconcile these two conflicting findings? Heart failure is a multi-step process that involves multiple organs, and we hypothesized that determining whether altering miR-25 alone could induce heart failure should provide a mechanistic basis for miR-25âs action in this process. Here, we show that overexpression of miR-25 in normal mice caused cardiomyocyte fibrosis and apoptosis but no obvious kidney impairment. By contrast, inhibition of miR-25 in normal mice led to hypertension, mild heart dilation, and severe kidney dysfunction. With the expectation that restoring miR-25 might ameliorate kidney injury, we demonstrated that increasing miR-25 reversed proteinuria and kidney fibrosis in diabetic nephropathy. MiR-25 expression in humans is initially decreased at the onset of heart failure but is later increased in end-stage heart failure. RNA sequencing of mouse kidneys with elevated and reduced miR-25 identified distinct alterations of a number of putative miR-25 target mRNAs, including those involved in the Ras signaling pathway, oxidant stress. In summary, differences in miR-25 expression during different stages of heart disease and its distinct roles in the heart and kidney, offer a new perspective for the role of miR-25 function in heart failure, which may begin to resolve this catch-22. Detect the mRNA alteration in wildtype and miR-25 agomir or antagomir treated mice

ORGANISM(S): Mus musculus

SUBMITTER: Binghai Zhao

PROVIDER: E-GEOD-83144 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.

Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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Alteration in microRNA-25 Balance Causes Heart and Kidney Impairment

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