Nitric Oxide Inhibits Glomerular TGF-β Signaling via SMOC-1

Dreieicher, Ellen; Beck, Karl‐Friedrich; Lazaroski, Sandra; Boosen, Meike; Tsalastra-Greul, Wasiliki; Beck, Martina; Fleming, Ingrid; Schaefer, Liliana; Pfeilschifter, Josef

doi:10.1681/asn.2008060653

Cited by 24 publications

(16 citation statements)

References 48 publications

(52 reference statements)

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“…We reported previously that ABT-627 prevents increases in TGF-␤ in this model (Sasser et al, 2007). Prior evidence also suggests that ET B receptors may possess antifibrotic action via endothelial NO synthase-derived NO signaling after inhibition of TGF-␤ (Dreieicher et al, 2009); so, the observation that the combined ET A/B antagonist was less effective was perhaps predictable. However, comparison of the two types of antagonists on measures of glomerular fibrosis in our studies was somewhat inconclusive because both ET A and ET A/B antagonists normalized activity of glomerular MMPs.…”

Section: Discussionmentioning

confidence: 63%

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Saleh

Pollock²,

Pollock³

2011

J Pharmacol Exp Ther

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Selective endothelin A (ET A ) and combined ET A and ET B receptor antagonists are being investigated for use in treating diabetic nephropathy. However, the receptor-specific mechanisms responsible for producing the potential benefits have not been discerned. Thus, we determined the actions of ET A and ET B receptors on measures of glomerular function and renal inflammation in the early stages of diabetic renal injury in rats through the use of selective and combined antagonists. Six weeks after streptozotocin (STZ)-induced hyperglycemia, rats were given 2R-(4-pyrrolidine-3-carboxylic acid hydrochloride (A-182086) (10 mg/kg/day), a combined ET A/B antagonist; or vehicle for 1 week. Sham controls received STZ vehicle (saline). Hyperglycemia led to significant proteinuria, increased glomerular permeability to albumin (P alb ), nephrinuria, and an increase in total matrix metalloprotease (MMP) and transforming growth factor-␤1 (TGF-␤1) activities in glomeruli. Plasma and glomerular soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were elevated after 7 weeks of hyperglycemia. Daily administration of both ABT-627 and A-182086 for 1 week significantly attenuated proteinuria, the increase in P alb , nephrinuria, and total MMP and TGF-␤1 activity. However, glomerular sICAM-1 and MCP-1 expression was attenuated with ABT-627, but not A-182086, treatment. In summary, both selective ET A and combined ET A/B antagonists reduced proteinuria and glomerular permeability and restored glomerular filtration barrier component integrity, but only ET A -selective blockade had antiinflammatory and antifibrotic effects. We conclude that selective ET A antagonists are more likely to be preferred for the treatment of diabetic kidney disease.

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Section: Discussionmentioning

confidence: 63%

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Saleh

Pollock²,

Pollock³

2011

J Pharmacol Exp Ther

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“…Low levels of nitric oxide (generated by endothelial nitric oxide synthase [eNOS]) induce expression of antioxidative genes, protect renal endothelial and mesangial cells from apoptosis and fibrosis (15,62,144,237,270,313), and promote normal renal hemodynamics. In endothelial cells, in addition to being tethered to the cell membrane, eNOS can also present on the cytosolic face of the outer mitochondrial membrane (84).…”

Section: Renal Vasculaturementioning

confidence: 99%

Oxidant Mechanisms in Renal Injury and Disease

Ratliff

Abdulmahdi

Pawar

et al. 2016

Antioxidants & Redox Signaling

512

513

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Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

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“…Moreover, one of the best experimental animal DN models is the diabetic eNOS -/- mouse [6,7,28-30]. While NO signaling in mesangial cells is complex and incompletely understood, it appears that NO produced in high amounts can stimulate redox signaling and cause downstream damage to cells, but when coupled with soluble guanylate cyclase actually leads to prosurvival and antifibrotic effects in mesangial cells [31]. A very recent report has found that NO suppresses expression of a profibrotic factor known as secreted modular calcium binding protein 1 (SMOC-1) [31].…”

Section: Mesangial Cell Signaling Abnormalitiesmentioning

confidence: 99%

Abnormalities in signaling pathways in diabetic nephropathy

Brosius

Khoury²,

Buller

et al. 2010

Expert Review of Endocrinology & Metabolism

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Diabetic nephropathy (DN) is characterized by a plethora of signaling abnormalities that together ultimately result in the clinical and pathologic hallmarks of DN, namely progressive albuminuria followed by a gradual decline in glomerular filtration rate leading to kidney failure, and accompanied by podocyte loss, progressive glomerular sclerosis and, ultimately, progressive tubulointerstitial fibrosis. Over the past few years, the general understanding of the abnormalities in signaling pathways that lead to DN has expanded considerably. In this review, some of the important pathways that appear to be involved in driving this process are discussed, with special emphasis on newer findings and insights. Newer concepts regarding signaling changes in bradykinin, mTOR, JAK/STAT, MCP-1, VEGF, endothelial nitric oxide synthase, activated protein C and other pathways are discussed. Keywordsdiabetes; glomerulus; matrix proteins; signaling Diabetic nephropathy (DN) is usually manifested clinically by gradually worsening albuminuria, followed by a decline in glomerular filtration rate, which over years or decades leads to end-stage kidney disease in many patients with Type 1 or Type 2 diabetes. The pathologic correlates of this process are glomerular podocyte damage and loss [1], followed by the gradual, inexorable scarring of the renal glomerulus and then a similar fibrosing process

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Nitric Oxide Inhibits Glomerular TGF-β Signaling via SMOC-1

Cited by 24 publications

References 48 publications

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Oxidant Mechanisms in Renal Injury and Disease

Abnormalities in signaling pathways in diabetic nephropathy

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