Suppression of mesangial cell proliferation and extracellular matrix production in streptozotocin-induced diabetic rats by Sp1 decoy oligodeoxynucleotide in vitro and in vivo.
Transcription factor Sp-1 is an important fibrogenic factor that is involved in the pathogenesis of diabetic nephropathy. In this study, we examined the effect of Sp1 decoy oligodeoxynucleotides (ODNs) on the extracellular matrix (ECM) gene expression in cultured rat mesangial cells (RMC) and streptozotocin (STZ)-induced diabetic rats. The ring-type Sp1 decoy ODNs significantly decreased ECM mRNA expression and Sp1 binding to the promoter region of these PDGF-induced genes in RMC. In addition, the decoy ODNs was introduced into the left renal artery of diabetic rat using the hemagglutinating virus of Japan (HVJ)-liposome mediated gene transfer method and effectively delivered to the kidney. On 14 days after ring-type Sp1 decoy ODNs injection, type IV collagen, fibronectin mRNA, and protein expression were markedly decreased, and the rate of urinary creatinine excretion was reduced in the ring-type Sp1 decoy ODNs-treated diabetic rats. These results indicated that the ring-type Sp1 decoy ODNs would be superior to P-Sp1 ODNs. Also, the R-Sp1 decoy ODN when introduced in vivo, effectively reduced ECM production during the progression of nephropathy. Therefore, ring-type Sp1 decoy is a promising tool for developing new therapeutic applications for progressive diabetic nephropathy.
Kang
Jeong Han
JH
Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Korea.
Chae
Young-Mi
YM
Park
Kwan-Kyu
KK
Kim
Cheorl-Ho
CH
Lee
In-Seon
IS
Chang
Young-Chae
YC
D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D024141:Collagen Type IV / Q000096:biosynthesis; D003404:Creatinine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000517:prevention & control* / Q000652:urine; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005353:Fibronectins / Q000096:biosynthesis; D005822:Genetic Vectors; D007269:Injections, Intra-Arterial; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery; D029082:Sendai virus / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D014161:Transduction, Genetic
D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D009838:Oligodeoxyribonucleotides; D010982:Platelet-Derived Growth Factor; C528043:R-Sp1 ODN; D016329:Sp1 Transcription Factor; D013311:Streptozocin; D003404:Creatinine