Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) determines the integrity of the extracellular matrix. TIMP3 is the most highly expressed tissue inhibitor of metalloproteinase (TIMP) in the kidney, but its function in renal disease is incompletely understood. In this study, TIMP3-/- mice demonstrated an age-dependent chronic tubulointerstitial fibrosis. After unilateral ureteral obstruction (UUO), young TIMP3-/- mice exhibited increased renal injury (tubular atrophy, cortical and medullary thinning, and vascular damage) compared with wild-type mice. In addition, TIMP3-/- mice had greater interstitial fibrosis; increased synthesis and deposition of type I collagen; increased activation of fibroblasts; enhanced apoptosis; and greater activation of MMP2, but not MMP9, after UUO. TIMP3 deficiency also led to accelerated processing of TNFalpha, demonstrated by significantly higher TACE activity and greater soluble TNFalpha levels by 3 d after UUO. The additional deletion of TNFalpha markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3-/-/TNFalpha-/- mice further abrogated postobstructive injury and prevented tubulointerestitial fibrosis. In humans, TIMP3 expression increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy. Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease.
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PMID:Loss of TIMP3 enhances interstitial nephritis and fibrosis. 1940 80

ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3(-/-) mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3(-/-) mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3(-/-) mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased. Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.
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PMID:Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. 2340 Dec 41

Diabetic nephropathy (DN) is the major cause of chronic kidney disease in developed countries and contributes significantly to increased morbidity and mortality among diabetic patients. Morphologically, DN is characterized by tubulo-interstitial fibrosis, thickening of the glomerular basement membrane and mesangial expansion mainly due to accumulation of extracellular matrix (ECM). ECM turnover is regulated by metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) activities. In diabetic conditions, TIMP3 expression in kidney is strongly reduced, but the causes of this reduction are still unknown. The aim of this study was to elucidate at least one of these mechanisms which relies on differential expression of TIMP3-targeting microRNAs (miRs) in a hyperglycemic environment either in vitro (MES13 cell line) or in vivo (mouse kidney and human biopsies). Among the TIMP3-targeting miRs, miR-21 and miR-221 were significantly upregulated in kidneys from diabetic mice compared to control littermates, and in a mesangial cell line grown in high glucose conditions. In human samples, only miR-21 expression was increased in kidney biopsies from diabetic patients compared to healthy controls. The expression of miR-217, which targets TIMP3 indirectly through downregulation of SirT1, was also increased in diabetic kidney and MES13 cell line. In agreement with these result, SirT1 expression was reduced in mouse and human diabetic kidneys as well as in MES13 mesangial cell line. TIMP3 deficiency has recently emerged as a hallmark of DN in mouse and human. In this study, we demonstrated that this reduction is due, at least in part, to increased expression of certain TIMP3-targeting miRs in diabetic kidneys compared to healthy controls. Unveiling the post-transcriptional mechanisms responsible for TIMP3 downregulation in hyperglycemic conditions may orient toward the use of this protein as a possible therapeutic target in DN.
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PMID:Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. 2379 4

This study aimed to study the roleof microRNA (miR)-181b and its target TIMP3 in the development of diabetic nephropathy (DMN) via inhibiting the apoptosis of mesangial cells. Real-time polymerase chain reaction (RT-PCR) was adopted to compare the miR-181b expression between subjects with diabetic nephropathy (DN) and normal control. In addition, luciferase assays were utilized to explore the regulatory relationship between TIMP3 and miR-181b. Real-time PCR and densitometry analysis were conducted to measure the levels of TIMP3 mRNA/protein in DMN or in cells treated by miR-181b inhibitors, miR-181b mimics, and TIMP3 siRNA. And the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was adopted to study the effect of miR-181b on cell survival and apoptosis. miR-181b expression was much higher in the DN group, and the results of computational analysis identified TIMP3 as a miR-181b target. The luciferase activity of cells transfected with wild-type TIMP3 and mutant2 TIMP3 was significantly reduced, whereas the luciferase activity of cells transfected with mutant1 TIMP3 was evidently higher. Furthermore, a negative regulatory relationship was established between TIMP3 and miR-181b expression with a correlation efficient of -0.5351. The levels of TIMP3 mRNA/protein expression were apparently increased in the DN group. In addition, the treatment of cells with miR-181b mimics and TIMP3 siRNA remarkably lowered the levels of TIMP3 mRNA/protein, whereas the transfection of cells with miR-181b inhibitors notably elevated the expression of TIMP3 mRNA/protein. miR-181b promoted the survival of cells and inhibited their apoptosis. The miR-181b expression was related to the development of DMN and could be used as a prognosis biomarker of DMN in the patients with DM.
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PMID:Dysregulation of microRNA-181b and TIMP3 is functionally involved in the pathogenesis of diabetic nephropathy. 3093 7

Diabetic nephropathy (DN) is one of the most important microvascular diseases in diabetic patients and has been the first cause of end stage renal disease (ESRD). In this study, we are aims to investigate the genetic mechanisms of lncRNA in the regulation of DN renal fibrosis. First, we have found that the expression of lncRNA TUG1 in db/db DN mice kidney tissue and high glucose-stimulated NRK-52E cells were down-regulated and the overexpression of lncRNA TUG1 could inhibit cell fibrosis of high glucose-stimulated of NRK-52E. Second, online software program Starbase predicts that miR-21 is a target gene of lncRNA TUG1 and TIMP3 is the target gene of miR-21, which have been verified by luciferase reporter assay and RNA Binding Protein Immunoprecipitation (RIP). Last, the renal fibrosis in DN mice and cell fibrosis in high glucose-stimulated NRK-52E cells were also evaluated. We have proven that overexpression of lncRNA TUG1 can promote the expression of TIMP3 through targeting the miR-21, thereby inhibiting cell fibrosis in high glucose-stimulated NRK-52E cells and renal fibrosis in DN mice. Our results indicated that lncRNA TUG1 could indirectly regulated the expression of TIMP3 by targeting miR-21. LncRNA TUG1 inhibited high glucose-stimulated NRK-52E cell fibrosis and renal fibrosis in DN mice, which provides a theoretical basis for the treatment of DN fibrosis.
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PMID:LncRNA TUG1 ameliorates diabetic nephropathy by inhibiting miR-21 to promote TIMP3-expression. 3193 79