Abstract |
Transforming growth factor-β (TGF-β) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-β activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-β 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-β 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-β activity through blockade of TSP1-dependent TGF-β activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-β.
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Authors | Ailing Lu, Mi Miao, Trenton R Schoeb, Anupam Agarwal, Joanne E Murphy-Ullrich |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 178
Issue 6
Pg. 2573-86
(Jun 2011)
ISSN: 1525-2191 [Electronic] United States |
PMID | 21641382
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Fibronectins
- Leu-Ser-Lys-Leu peptide
- Peptides
- Smad2 Protein
- Smad2 protein, mouse
- Thrombospondin 1
- Transforming Growth Factor beta
- Creatinine
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Topics |
- Albuminuria
(complications, pathology, urine)
- Amino Acid Sequence
- Animals
- Creatinine
(urine)
- Dermis
(drug effects, pathology)
- Diabetic Nephropathies
(complications, drug therapy, pathology, urine)
- Disease Models, Animal
- Fibronectins
(metabolism)
- Inflammation
(complications, pathology)
- Injections, Intraperitoneal
- Kidney
(drug effects, metabolism, pathology)
- Mice
- Mice, Inbred C57BL
- Molecular Sequence Data
- Peptides
(administration & dosage, chemistry, pharmacology, therapeutic use)
- Phosphorylation
(drug effects)
- Proteinuria
(complications, prevention & control, urine)
- Signal Transduction
(drug effects)
- Smad2 Protein
(metabolism)
- Thrombospondin 1
(metabolism)
- Transforming Growth Factor beta
(antagonists & inhibitors, urine)
- Wound Healing
(drug effects)
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