Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy

Fujimoto, M.; Maezawa, Yoshiro; Yokote, Koutaro; Joh, Kensuke; Kobayashi, Kazuki; Kawamura, Hajime; Nishimura, Motonobu; Roberts, Anita B.; Saitō, Yasushi; Mori, Seijiro

doi:10.1016/s0006-291x(03)00885-4

Cited by 181 publications

(149 citation statements)

References 27 publications

Supporting

Mentioning

138

Contrasting

Unclassified

Order By: Relevance

“…In vitro, increased Smad2 phosphorylation in consequence of elevated TGF-␤1 expression has been reported in rat tubular epithelial and mesangial cells in high-glucose culture (45). Furthermore, mice lacking Smad3 and made diabetic by STZ administration are protected against glomerulopathy, as assessed by basement membrane thickening, ␣3 (IV) collagen mRNA expression, albuminuria, and decreased GFR (46). These data support a role for Smads in diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 57%

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-␤1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-␤1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-␤1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-␤1. Neither TGF-␤1 bioactivity nor TGF-␤ receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti-TGF-␤1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF-␤ expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKC␦-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKC␤ and ␦ kinase assay. High glucose increased expression of several PKC isozymes, but only PKC␦ showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKC␦ inhibition during glucose conditioning abrogated enhanced ␣1(I) collagen mRNA and promoter induction by TGF-␤1. Taken together, these data strongly suggest that heightened ERK and PKC␦ activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-␤1 and increased extracellular matrix production in mesangial cells.

show abstract

Section: Discussionsupporting

confidence: 57%

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Elevated expression of TGF-␤ 1 is a major stimulant for ECM accumulation by mesangial cells through regulation of genes encoding ECM, PAI-1, and other proteins through Smads and extracellular signal-regulated kinase (ERK) (13,17,18,19,29,36,44,57,68,69,71). In this study, we found for the first time that two initial effects of high ambient glucose, the generation of ROS by NADPH oxidase and activation of PKC-are dependent on signal transduction initiated by TGF-␤ 1 .…”

Section: Discussionmentioning

confidence: 71%

“…Thus in high glucose Smad2/3 phosphorylation and nuclear translocation are observed in mesangial cells grown in tissue culture and in animal models of diabetic nephropathy (29,47). Eliminating Smad function prevents high glucose-induced collagen gene expression in mesangial cells and mesangial expansion in mice with streptozotocin-induced diabetes (13,57).…”

mentioning

confidence: 99%

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β₁ signaling in mesangial cells

Xia

Wang²,

Munk³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…In mouse models of diabetes, no specific histopathology criteria associated with diabetic nephropathy have been formulated. For example, thickening of the glomerular basement membrane has been reported in several but not all mouse models (33). Furthermore, nodular glomerular sclerosis generally is absent in mice as is arteriolar hyalinosis, which are two features that classically are seen only in humans with advanced diabetic nephropathy (34).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

show abstract

Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy

Cited by 181 publications

References 27 publications

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β₁ signaling in mesangial cells

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Contact Info

Product

Resources

About

Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy

Cited by 181 publications

References 27 publications

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Contact Info

Product

Resources

About

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β₁ signaling in mesangial cells