scholarly journals Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes

2008 ◽  
Vol 295 (2) ◽  
pp. F605-F617 ◽  
Author(s):  
Hang Yuan ◽  
Linda Lanting ◽  
Zhong-Gao Xu ◽  
Shu-Lian Li ◽  
Piotr Swiderski ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Mouse Model ◽  
Tissue Growth ◽  
Type I ◽  
Small Interfering Rnas ◽  
Matrix Deposition

We previously showed that the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate acid metabolism is involved in multiple events related to diabetic nephropathy (DN), including glomerular hypertrophy and extracellular matrix deposition (Kang SW, Adler SG, Nast CC, LaPage J, Gu JL, Nadler JL, Natarajan R. Kidney Int 59: 1354–1362, 2001; Kang SW, Natarajan R, Shahed A, Nast CC, LaPage J, Mundel P, Kashtan C, Adler SG. J Am Soc Nephrol 14: 3178–3187, 2003; Kim YS, Lanting L, Adler SG, Natarajan R. Kindney Int 64: 1702–1714, 2003; Reddy MA, Adler SG, Kim YS, Lanting L, Rossi JJ, Kang SW, Nadler JL, Shahed A, Natarajan R. Am J Physiol Renal Physiol 283: F985–F994, 2002). In this study, we investigated whether in vivo delivery of small interfering RNAs (siRNAs) targeting 12/15-LO can ameliorate renal injury and DN in a streptozotocin-injected mouse model of type 1 diabetes. To achieve greater in vivo access and siRNA expression in the kidney, we used double-stranded 12/15-LO siRNA oligonucleotides conjugated with cholesterol. Diabetic DBA/2J mice were injected subcutaneously with either cholesterol-tagged 12/15-LO siRNA, mismatched control siRNA, or vehicle alone, twice weekly for 7 wk. Relative to controls, mice that received 12/15-LO siRNA showed significant reduction in albuminuria, kidney-to-body weight ratios, glomerular mesangial matrix expansion, renal structural damage, and monocyte/macrophage infiltration. These effects were associated with lower renal cortical or glomerular levels of profibrotic markers transforming growth factor-β, connective tissue growth factor, type I and type IV collagens, plasminogen activator inhibitor 1, and fibronectin. The diabetes-induced increase in glomerular cyclin-dependent kinase inhibitors that are associated with hypertrophy was also prevented by siRNA administration. Our results show for the first time that systemic delivery of cholesterol-tagged siRNAs targeting 12/15-LO has renoprotective effects under diabetic conditions and therefore could be a novel therapeutic approach for DN.

scholarly journals Cellular Basis of Diabetic Nephropathy: II. The Transforming Growth Factor-  System and Diabetic Nephropathy Lesions in Type 1 Diabetes

Diabetes ◽  
2002 ◽  
Vol 51 (12) ◽  
pp. 3577-3581 ◽  
Author(s):  
C. Huang ◽  
Y. Kim ◽  
M. L. A. Caramori ◽  
A. J. Fish ◽  
S. S. Rich ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cellular Basis ◽  
Factor System

scholarly journals In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13235 ◽  
Author(s):  
Daniel J. Moore ◽  
Jozef Zienkiewicz ◽  
Peggy L. Kendall ◽  
Danya Liu ◽  
Xueyan Liu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Model ◽  
Nuclear Import

scholarly journals Senescence marker protein‐30/gluconolactonase deficiency exacerbates diabetic nephropathy through tubular injury in a mouse model of type 1 diabetes

2014 ◽  
Vol 6 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Hiroshi Okada ◽  
Takafumi Senmaru ◽  
Michiaki Fukui ◽  
Yoshitaka Kondo ◽  
Akihito Ishigami ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Marker Protein ◽  
Tubular Injury

scholarly journals Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy

2005 ◽  
Vol 67 (6) ◽  
pp. 2325-2329 ◽  
Author(s):  
Steen Andersen ◽  
Frans A. van Nieuwenhoven ◽  
Lise Tarnow ◽  
Peter Rossing ◽  
Kasper Rossing ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth

scholarly journals Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice

2017 ◽  
Vol 312 (5) ◽  
pp. L741-L747 ◽  
Author(s):  
Hongge Ma ◽  
Shupei Qiao ◽  
Zeli Wang ◽  
Shuai Geng ◽  
Yufang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Genetically Engineered ◽  
Hek293 Cells ◽  
High Morbidity ◽  
Type I

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.

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