Antihypertensive effects of chronic anti-TGF-β antibody therapy in Dahl S rats

Dahly, Annette J.; Hoagland, Kimberly M.; Flasch, Averia K.; Jha, Sharda; Ledbetter, Steven; Roman, Richard J.

doi:10.1152/ajpregu.00098.2002

Cited by 92 publications

(66 citation statements)

References 40 publications

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“…However, similar findings were reported in older Dahl salt-sensitive hypertensive rats with established glomerular disease: anti-TGF-␤ antibody (1D11) blocked proteinuria and reduced renal TGF-␤ activity but had no effect on glomerulosclerosis or hypertrophy. 67 It was suggested that the reduction in proteinuria without reduced glomerulosclerosis could be due to blockade of the effects of TGF-␤ on glomerular permeability but an inability of the antibody to reverse established fibrosis. 63,67 To address the effect of long-term LSKL therapy on other TGF-␤-mediated functions in diabetes, we studied dermal wound healing in a well-established model of diabetic wound healing in type 2 diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

“…67 It was suggested that the reduction in proteinuria without reduced glomerulosclerosis could be due to blockade of the effects of TGF-␤ on glomerular permeability but an inability of the antibody to reverse established fibrosis. 63,67 To address the effect of long-term LSKL therapy on other TGF-␤-mediated functions in diabetes, we studied dermal wound healing in a well-established model of diabetic wound healing in type 2 diabetic mice. 44 TGF-␤ signaling is known to be impaired in diabetic skin wounds, resulting in reduced macrophage chemoattraction, angiogenesis, and extracellular matrix deposition with accelerated reepithelialization.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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“…Dahly et al (40) injected anti-TGF-␤ antibody into salt-loaded Dahl-S rats every day for 2 wk and found a significant decrease in BP, proteinuria, and degree of glomerulosclerosis and renal interstitial fibrosis. Polyamide completely inhibited the increases in proteinuria and albuminuria in salt-loaded Dahl-S rats, along with suppression of TGF-␤1 staining in glomeruli and nephrotubuli.…”

Section: Discussionmentioning

confidence: 99%

Development of Gene Silencing Pyrrole-Imidazole Polyamide Targeting the TGF-β1 Promoter for Treatment of Progressive Renal Diseases

Matsuda¹,

Fukuda²,

Ueno³

et al. 2006

Journal of the American Society of Nephrology

102

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Pyrrole-imidazole (Py-Im) polyamides are nuclease-resistant novel compounds that inhibit gene expression by binding to the minor groove of DNA. A Py-Im polyamide that targets rat TGF-␤1 was designed as a gene-silencing agent for progressive renal diseases, and the distribution and the effects of this polyamide on renal injury were examined in Dahl-salt sensitive (Dahl-S) rats. For identification of transcription factor binding elements for activation of the rat TGF-␤1 gene, recombinant TGF-␤1 reporter plasmids were transfected into HEK-293 cells, and promoter activity was measured. Py-Im polyamide was designed to the activator protein-1 binding site of the rat TGF-␤1 promoter. This Py-Im polyamide showed strong, fast, and specific binding to the target DNA in gel mobility shift and Biacore assays. Py-Im polyamide significantly inhibited TGF-␤1 promoter activity and expression of TGF-␤1 mRNA and protein in rat mesangial cells. Intravenously administered fluorescein-labeled polyamide distributed to the kidney of rats. Py-Im polyamide significantly inhibited expression of TGF-␤1 mRNA and protein in the renal cortex of Dahl-S rats and reduced the increase in urinary protein and albumin in Dahl-S rats independent of changes in blood pressure. These results indicate that Py-Im polyamide that targets TGF-␤1 will be a novel gene-silencing agent for the TGF-␤1-associated diseases, including progressive renal diseases.

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“…This can lead to renal scarring and end-stage renal disease in patients with hypertension and diabetes mellitus. On the other hand, chronic anti-TGF-b antibody reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in Dahl salt-sensitive rats (Dhaly et al, 2002). In vitro studies revealed that neutralizing TGF-b could inhibit increased synthesis of collagen by cultured mesangial cells in the presence of high glucose.…”

Section: Transforming Growth Factor-b No and Hypertensionmentioning

confidence: 97%

Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-β to prevent human essential hypertension

Das¹

2004

Eur J Clin Nutr

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Patients with uncontrolled essential hypertension have elevated concentrations of superoxide anion (O 2 ÀK ), hydrogen peroxide (H 2 O 2 ), lipid peroxides, endothelin, and transforming growth factor-b (TGF-b) with a simultaneous decrease in endothelial nitric oxide (eNO), superoxide dismutase (SOD), vitamin E, and long-chain polyunsaturated fatty acids (LCPUFAs). Physiological concentrations of angiotensin II activate NAD(P)H oxidase and trigger free radical generation (especially that of O 2 ÀK ). Normally, angiotensin II-induced oxidative stress is abrogated by adequate production and release of eNO, which quenches O 2 ÀK to restore normotension. Angiotensin II also stimulates the production of endothelin and TGF-b. TGF-b enhances NO generation, which in turn suppresses TGF-b production. Thus, NO has a regulatory role on TGF-b production and is also a physiological antagonist of endothelin. Antihypertensive drugs suppress the production of O 2 ÀK and TGF-b and enhance eNO synthesis to bring about their beneficial actions. LCPUFAs suppress angiotensin-converting enzyme (ACE) activity, reduce angiotensin II formation, enhance eNO generation, and suppress TGF-b expression. Perinatal supplementation of LCPUFAs decreases insulin resistance and prevents the development of hypertension in adult life, whereas deficiency of LCPUFAs in the perinatal period results in raised blood pressure later in life. Patients with essential hypertension have low concentrations of various LCPUFAs in their plasma phospholipid fraction. Based on this, it is proposed that LCPUFAs serve as endogenous regulators of ACE activity, O 2 ÀK , eNO generation, and TGF-b expression. Further, LCPUFAs have actions similar to statins, inhibit (especially o-3 fatty acids) cyclooxygenase activity and suppress the synthesis of proinflammatory cytokines, and activate the parasympathetic nervous system, all actions that reduce the risk of major vascular events. Hence, it is proposed that availability of adequate amounts of LCPUFAs during the critical periods of growth prevents the development of hypertension in adulthood.

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Antihypertensive effects of chronic anti-TGF-β antibody therapy in Dahl S rats

Cited by 92 publications

References 40 publications

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Development of Gene Silencing Pyrrole-Imidazole Polyamide Targeting the TGF-β1 Promoter for Treatment of Progressive Renal Diseases

Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-β to prevent human essential hypertension

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