In vivo delivery of gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7

Qingxian Zhang, Yonghong Shi, Jun Wada, Sandra M. Malakauskas, Maodong Liu, Yunzhuo Ren, Chunyang Du, Huijun Duan, Yingmin Li, Ying Li, Yanling Zhang

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor- b1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy.

Original languageEnglish
Article numbere11709
JournalPLoS One
Volume5
Issue number7
DOIs
Publication statusPublished - 2010

Fingerprint

Bone Morphogenetic Protein 7
diabetic nephropathy
bone morphogenetic proteins
Diabetic Nephropathies
small interfering RNA
Small Interfering RNA
plasmids
Plasmids
therapeutics
Cell proliferation
Kidney
kidneys
Collagen
collagen
Apoptosis
cell proliferation
apoptosis
Bone Morphogenetic Proteins
Cell Proliferation
Smad Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

In vivo delivery of gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. / Zhang, Qingxian; Shi, Yonghong; Wada, Jun; Malakauskas, Sandra M.; Liu, Maodong; Ren, Yunzhuo; Du, Chunyang; Duan, Huijun; Li, Yingmin; Li, Ying; Zhang, Yanling.

In: PLoS One, Vol. 5, No. 7, e11709, 2010.

Research output: Contribution to journalArticle

Zhang, Qingxian ; Shi, Yonghong ; Wada, Jun ; Malakauskas, Sandra M. ; Liu, Maodong ; Ren, Yunzhuo ; Du, Chunyang ; Duan, Huijun ; Li, Yingmin ; Li, Ying ; Zhang, Yanling. / In vivo delivery of gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. In: PLoS One. 2010 ; Vol. 5, No. 7.
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