| First Author | Lu A | Year | 2011 |
| Journal | Am J Pathol | Volume | 178 |
| Issue | 6 | Pages | 2573-86 |
| PubMed ID | 21641382 | Mgi Jnum | J:173296 |
| Mgi Id | MGI:5013837 | Doi | 10.1016/j.ajpath.2011.02.039 |
| Citation | Lu A, et al. (2011) Blockade of TSP1-Dependent TGF-beta Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy. Am J Pathol 178(6):2573-86 |
| abstractText | Transforming growth factor-beta (TGF-beta) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-beta activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-beta 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-beta 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-beta activity through blockade of TSP1-dependent TGF-beta activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-beta. |
