Role of Smad4 on TGF-β–induced extracellular matrix stimulation in mesangial cells

Tsuchida, Kenichi; Zhu, Yanqing; Senthuran, Siva; Dunn, Stephen; Sharma, Kumar

doi:10.1046/j.1523-1755.2003.00009.x

Cited by 99 publications

(94 citation statements)

References 41 publications

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Section: Diabetic Nephropathy and Tgf-␤ Actionsmentioning

confidence: 99%

“…Evidence shows that ECM genes including collagen type I-␣1 and 2 (Col1a1/a2) are regulated by TGF-␤ via Smads in MCs (96,100). Interaction of TGF-␤ with its receptors induces the phosphorylation and nuclear translocation of the receptor-regulated Smad2/3 transcription factors (98,99,101) to regulate gene expression (95,96,100,102). TGF-␤ also activates the phosphoinositide-3-kinase/Akt kinase pathway in MCs (103)(104)(105)(106)(107)(108)(109)(110), and this has been implicated in its fibrotic responses, such as expression of collagen and fibronectin (105,106).…”

Section: Diabetic Nephropathy and Tgf-␤ Actionsmentioning

confidence: 99%

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MicroRNAs and Their Role in Progressive Kidney Diseases

Kato

Arce

Natarajan

2009

Clinical Journal of the American Society of Nephrology

146

105

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MicroRNAs (miRs) are a family of short non-coding RNAs. These endogenously produced factors have been shown to play important roles in gene regulation. The discovery of miRs has greatly expanded our knowledge of gene regulation at the posttranscriptional level. miRs inhibit target gene expression by blocking protein translation or by inducing mRNA degradation and therefore have the potential to modulate physiologic and pathologic processes. The imperative need to determine their cellular targets and disease relevance has sparked an unprecedented explosion of research in the miR field. Recent findings have revealed critical functions for specific miRs in cellular events such as proliferation, differentiation, development, and immune responses and in the regulation of genes relevant to human diseases. Of particular interest to renal researchers are recent reports that key miRs are highly expressed in the kidney and can act as effectors of TGF-␤ actions and high glucose in diabetic kidney disease. Moreover, podocyte-specific deletion of Dicer, a key enzyme involved in miR biogenesis, led to proteinuria and severe renal dysfunction in mice. Hence, studies aimed at determining the in vitro and in vivo functions of miRs in the kidney could determine their value as therapeutic targets for progressive renal glomerular and tubular diseases. Translational approaches could be facilitated by the development of effective inhibitors of specific miRs and methods for optimal delivery of anti-miRs to the kidney. The major goal of this review is to highlight key functions of these miRs and their relationships to human diseases, with special emphasis on diabetic kidney disease.

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Section: Diabetic Nephropathy and Tgf-␤ Actionsmentioning

confidence: 99%

Section: Diabetic Nephropathy and Tgf-␤ Actionsmentioning

confidence: 99%

MicroRNAs and Their Role in Progressive Kidney Diseases

Kato

Arce

Natarajan

2009

Clinical Journal of the American Society of Nephrology

146

105

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“…Collagen 1-␣ 1 and -2 (Col1a1 and -2) and other ECM genes are regulated in MC by TGF-␤ via Smads (7,8). The regulation of collagen by TGF-␤ in MC also is mediated by mitogen-activated protein kinases (MAPKs) such as p38 and ERKs (9-11).…”

mentioning

confidence: 99%

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors

Kato¹,

Zhang

Wang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

668

691

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Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-␣ 1 and -2 (Col1a1 and -2). Transforming growth factor ␤1 (TGF-␤), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-␤ increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, ␦EF1. TGF-␤ treatment or short hairpin RNAs targeting ␦EF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-␤ also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to ␦EF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-␤ in MMC. TGF-␤ treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3 UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with ␦EF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-␤ and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-␤-induced Col1a2 expression by down-regulating E-box repressors.diabetic nephropathy ͉ mesangial cells ͉ small noncoding RNA ͉ transforming growth factor ␤1 D iabetic nephropathy (DN) is the most common cause of kidney failure in patients with diabetes mellitus. The major characteristics of DN include glomerular basement-membrane thickening, mesangial expansion and hypertrophy, and an accumulation of extracellular matrix (ECM) proteins (1). Evidence shows that transforming growth factor ␤1 (TGF-␤) levels are increased under diabetic conditions in renal cells, including mesangial cells (MC), can up-regulate ECM proteins such as collagens (2, 3), and also can promote MC survival and oxidant stress (4).To date, Smad transcription factors have been shown to be the major effectors of TGF-␤ signaling (5, 6). Collagen 1-␣ 1 and -2 (Col1a1 and -2) and other ECM genes are regulated in MC by TGF-␤ via Smads (7,8). The regulation of collagen by TGF-␤ in MC also is mediated by mitogen-activated protein kinases (MAPKs) such as p38 and ERKs (9-11). However, the molecular mechanisms by which TGF-␤ regulates ECM genes still are not understood fully. The collagen gene has E-box elements in the far upstream enhancer region (12, 13). An E-box repressor, ␦EF1, is a key inhibitor of E-cadherin (14) and E2-box transcription factors such as Nkx2.5 (12). Moreover, it is a known repressor of collagen type 1 and type 2 genes in other cells (12, 13), but its role in MC is ...

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“…10 It is now widely accepted that up-regulation of TGF-b1 is one of the key factors responsible for the increased fibrotic changes in chronic renal failure. 16 The contribution of TGF-b1 to the pathology of glomerulosclerosis had been established by both in vivo studies and by analyses of glomerular cells in culture.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] The up-regulation of TGF-b1 is one of the key factors responsible for chronic changes in renal function. 10 The 5/6 nephrectomized rat is a commonly used experimental model in the study of renal diseases. After 5/6 nephrectomy the number of nephrons are reduced, causing glomerular hyperperfusion, hypertension, and hyperfiltration, which eventually cause chronic renal failure.…”

Section: Introductionmentioning

confidence: 99%

Pathological changes, TGF-β1 expression, and the effects of hepatocyte growth factor in 5/6 nephrectomized rats

Wang

Yang

et al. 2013

Renal Failure

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Several studies have shown that hepatocyte growth factor (HGF) ameliorates chronic renal failure, but its mechanism of action is unclear. This study was designed to test the delivery of HGF in the PCI-neo vector, using the 5/6 nephrectomized rat as a model for chronic renal failure, and to confirm that this protective function is associated with decreased protein expression of transforming growth factor-beta1 (TGF-b1). Rats were randomly divided into the following groups: Control (untreated), PCI-neo (vector control), 5/6 nephrectomy, and PCI-neo-HGF. Rats were sacrificed at both the fifth and ninth week after 5/6 nephrectomy. Kidney specimens were used for pathological examination (hematoxylin-eosin staining), and detection of TGF-b1 protein (Western blot and immunohistochemistry) expression. Blood urea nitrogen, serum creatinine, and 24-h urinary protein excretion (UPE) were increased, renal interstitium was seriously injured, and TGF-b1 protein expression was elevated in 5/6 nephrectomized rats compared to control rats at either time point. Red blood cell and hemoglobin levels decreased in the ninth week after 5/6 nephrectomy. PCI-neo-HGF expression ameliorated the aforementioned changes and decreased TGF-b1 expression, not only in the fifth week, but also in the ninth week after surgery. The process of renal injury in the 5/6 nephrectomized rat was consistent with that of chronic renal failure. The increase in TGF-b1 expression was maintained after 5/6 nephrectomy. HGF relieved chronic renal failure, this protection was associated with down-regulation of TGF-b1 protein expression, and the protective effects were long-term and stable after 5/6 nephrectomy.Keywords 5/6 nephrectomized rats, hepatocyte growth factor, pathological changes, PCI-neo, transforming growth factor-b1History

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Role of Smad4 on TGF-β–induced extracellular matrix stimulation in mesangial cells

Cited by 99 publications

References 41 publications

MicroRNAs and Their Role in Progressive Kidney Diseases

MicroRNAs and Their Role in Progressive Kidney Diseases

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors

Pathological changes, TGF-β1 expression, and the effects of hepatocyte growth factor in 5/6 nephrectomized rats

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