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

Zhang Q, Shi Y, Wada J, Malakauskas SM, Liu M, Ren Y, Du C, Duan H, Li Y, Li Y, Zhang Y - PLoS ONE (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Third Hospital, Hebei Medical University, Shijiazhuang, China.

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-beta1 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.

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BMP-7 expression in diabetic kidneys assessed by Western blotting.Compared with non-diabetic control mice (N), mice in the STZ group display similar BMP-7 kidney expression levels at week-1 and week-2. The BMP-7 expression in the STZ group gradually decreased to a significantly lower level at week-12. No significant effect is seen on the expression of BMP-7 in diabetic kidneys by the treatment with gremlin siRNA plasmid. (* p<0.05). N = 6 mice per group.
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pone-0011709-g004: BMP-7 expression in diabetic kidneys assessed by Western blotting.Compared with non-diabetic control mice (N), mice in the STZ group display similar BMP-7 kidney expression levels at week-1 and week-2. The BMP-7 expression in the STZ group gradually decreased to a significantly lower level at week-12. No significant effect is seen on the expression of BMP-7 in diabetic kidneys by the treatment with gremlin siRNA plasmid. (* p<0.05). N = 6 mice per group.

Mentions: As shown in Figure 4, expression of BMP-7 in kidney cortical homogenates from the STZ group markedly decreased compared to that of the control group at week-12. No obvious effect of gremlin siRNA plasmid on BMP-7 expression in the diabetic kidney was seen, which indicated that BMP-7 expression in the kidneys of STZ-induced diabetic rats may not be directly regulated by Gremlin.


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

Zhang Q, Shi Y, Wada J, Malakauskas SM, Liu M, Ren Y, Du C, Duan H, Li Y, Li Y, Zhang Y - PLoS ONE (2010)

BMP-7 expression in diabetic kidneys assessed by Western blotting.Compared with non-diabetic control mice (N), mice in the STZ group display similar BMP-7 kidney expression levels at week-1 and week-2. The BMP-7 expression in the STZ group gradually decreased to a significantly lower level at week-12. No significant effect is seen on the expression of BMP-7 in diabetic kidneys by the treatment with gremlin siRNA plasmid. (* p<0.05). N = 6 mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908623&req=5

pone-0011709-g004: BMP-7 expression in diabetic kidneys assessed by Western blotting.Compared with non-diabetic control mice (N), mice in the STZ group display similar BMP-7 kidney expression levels at week-1 and week-2. The BMP-7 expression in the STZ group gradually decreased to a significantly lower level at week-12. No significant effect is seen on the expression of BMP-7 in diabetic kidneys by the treatment with gremlin siRNA plasmid. (* p<0.05). N = 6 mice per group.
Mentions: As shown in Figure 4, expression of BMP-7 in kidney cortical homogenates from the STZ group markedly decreased compared to that of the control group at week-12. No obvious effect of gremlin siRNA plasmid on BMP-7 expression in the diabetic kidney was seen, which indicated that BMP-7 expression in the kidneys of STZ-induced diabetic rats may not be directly regulated by Gremlin.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Third Hospital, Hebei Medical University, Shijiazhuang, China.

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-beta1 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.

Show MeSH
Related in: MedlinePlus