Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies

Takao, Masaki; Stambe, Cosimo; Hill, Prudence A.; Dowling, John P.; Atkins, Robert C.; Nikolic-Paterson, David J.

doi:10.1097/01.asn.0000130623.66271.67

Cited by 62 publications

(58 citation statements)

References 33 publications

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“…Our results are also consistent with those of Albrecht et al [35], who reported that chronic treatment with approximately 1.5 g kg −1 day −1 of arginine (chemical form unspecified) showed significant reduction in transplant-associated glomerular sclerosis in rats. These authors demonstrated a significant reduction in the expression of interstitial alpha smooth muscle actin in L-argininetreated animals, which in turn is thought to be partly responsible for the increased interstitial fibrosis associated with sclerotic damage [36]. Similarly, Vos et al [37], using an allograft model of kidney damage, also reported that L-arginine supplementation can improve the glomerular filtration rate and minimise glomerular oedema.…”

Section: Discussionmentioning

confidence: 81%

A novel complex of arginine–silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats

2005

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Aims/hypothesis: The metabolic syndrome, with associated vasculopathy, is a major cause of cardiovascular disease and nephropathy. Impaired nitric oxide (NO) metabolism and endothelial function is an important component of the disease process. Increasing the availability of arginine, the precursor of NO, might enhance vascular function and protect against end-stage disease. Materials and methods: Insulin-resistant JCR:LA-cp rats were treated with arginine-silicate-inositol complex or arginine-HCl at 1.0 g kg −1 day −1 (expressed as arginine-HCl) from 8 to 13 weeks of age. The contractile/relaxant function of thoracic aortae and coronary arteries was assessed in vitro. Kidneys were assessed for severity of glomerular sclerosis. Results: Arginine-silicate complex, but not arginineHCl, normalised the hypercontractile response of the aorta to phenylephrine via an NO-dependent pathway. Coronary artery function, as indicated by reactive hyperaemia to warm ischaemia, was enhanced by both arginine compounds. In addition, the arginine-silicate complex increased coronary vasodilatation in response to bradykinin. Glomerular sclerosis was significantly reduced in rats treated with the arginine-silicate complex. Conclusions/ interpretation: Treatment with exogenous arginine, in an efficiently absorbed form, improves vascular function and reduces nephropathy in an animal model of insulin resistance and cardiovascular disease, via mechanism(s) independent of insulin concentration. Enhancement of NO metabolism through increased availability of the precursor arginine appears to offer protection against microand macrovascular disease associated with the metabolic syndrome and insulin resistance.

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Section: Discussionmentioning

confidence: 81%

A novel complex of arginine–silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats

2005

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“…In the kidney, ERK1/2 is expressed in all nephron segments and plays an important role in multiple physiological (33) and pathological processes (30). In contrast to other nephron segments, ERK1/2 appears to have basal activity in distal nephron cells (31,34), consistent with tonic inhibition of Na ϩ transport by the ERK pathway. It is well demonstrated that the components of the MAPK cascade (Raf-1, MEK1/2, and ERK1/2, in this case) exist in a multiprotein complex to permit the cell to perform coordinate regulation of several simultaneous possibly divergent signals at multiple levels (35).…”

Section: Gilz1 and Sgk1 Synergistically Stimulate Enac Cell Surface Ementioning

confidence: 88%

“…4). This association of PI3K and Raf-1 pathway components into an ion transport regulatory complex provides a novel mechanism for achieving signaling specificity (9,10,(28)(29)(30)(31). Through this mechanism, ion transport can be selectively stimulated while having little or no effect on context-inappropriate targets.…”

Section: Gilz1 and Sgk1 Synergistically Stimulate Enac Cell Surface Ementioning

confidence: 99%

Epithelial sodium channel regulated by differential composition of a signaling complex

Soundararajan¹,

Melters²,

Shih³

et al. 2009

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

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Hormonal control of transepithelial sodium (Na ؉ ) transport utilizes phosphatidylinositide 3 -kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na ؉ transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum-and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K-and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na ؉ transport without inappropriately activating other cell functions.glucocorticoid-induced leucine zipper protein ͉ Nedd4-2 ͉ Raf-1 ͉ serum-and glucocorticoid-induced kinase 1

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“…The glomerular ERK1/2 was maximally activated on day 6 and represents a putative mediator of the proliferative response in mesangioproliferative GN. In addition, ERK1/2 activation in human glomerulopathies is associated with cell proliferation, histological lesions, and renal dysfunction (Masaki et al, 2004). Thus, these studies showing ERK activation in damaged glomeruli raise the possibility that ERK1/2 is an important signal molecule for acute inflammation-induced cellular proliferation in GN.…”

Section: Mapks In Gnmentioning

confidence: 89%

Renin-Angiotensin System Activation and Extracellular Signal-Regulated Kinases in Glomerulonephritis

Urushihara¹,

Kinoshita²

2011

An Update on Glomerulopathies - Etiology and Pathogenesis

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Activation of the Extracellular-Signal Regulated Protein Kinase Pathway in Human Glomerulopathies

Cited by 62 publications

References 33 publications

A novel complex of arginine–silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats

A novel complex of arginine–silicate improves micro- and macrovascular function and inhibits glomerular sclerosis in insulin-resistant JCR:LA-cp rats

Epithelial sodium channel regulated by differential composition of a signaling complex

Renin-Angiotensin System Activation and Extracellular Signal-Regulated Kinases in Glomerulonephritis

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