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Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes

Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 dele...

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Autores principales: Wang, Zongwei, Cheng, Zhiyong, Cristofaro, Vivian, Li, Jijun, Xiao, Xingyuan, Gomez, Pablo, Ge, Rongbin, Gong, Edward, Strle, Klemen, Sullivan, Maryrose P., Adam, Rosalyn M., White, Morris F., Olumi, Aria F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402324/
https://www.ncbi.nlm.nih.gov/pubmed/22688336
http://dx.doi.org/10.2337/db11-1763
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author Wang, Zongwei
Cheng, Zhiyong
Cristofaro, Vivian
Li, Jijun
Xiao, Xingyuan
Gomez, Pablo
Ge, Rongbin
Gong, Edward
Strle, Klemen
Sullivan, Maryrose P.
Adam, Rosalyn M.
White, Morris F.
Olumi, Aria F.
author_facet Wang, Zongwei
Cheng, Zhiyong
Cristofaro, Vivian
Li, Jijun
Xiao, Xingyuan
Gomez, Pablo
Ge, Rongbin
Gong, Edward
Strle, Klemen
Sullivan, Maryrose P.
Adam, Rosalyn M.
White, Morris F.
Olumi, Aria F.
author_sort Wang, Zongwei
collection PubMed
description Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions (double knockout [DKO]), which develops type 2 diabetes. Bladders of DKO animals exhibited detrusor overactivity at an early stage: increased frequency of nonvoiding contractions during bladder filling, decreased voided volume, and dispersed urine spot patterns. In contrast, older animals with diabetes exhibited detrusor hypoactivity, findings consistent with clinical features of diabetes in humans. The tumor necrosis factor (TNF) superfamily genes were upregulated in DKO bladders. In particular, TNF-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α augmented the contraction of primary cultured bladder smooth muscle cells through upregulating Rho kinase activity and phosphorylating myosin light chain. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of Rho A signaling and reversed the bladder dysfunction, without affecting hyperglycemia. TNFRI combined with the antidiabetic agent, metformin, improved DBD beyond that achieved with metformin alone, suggesting that therapies targeting TNF-α may have utility in reversing the secondary urologic complications of type 2 diabetes.
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spelling pubmed-34023242013-08-01 Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes Wang, Zongwei Cheng, Zhiyong Cristofaro, Vivian Li, Jijun Xiao, Xingyuan Gomez, Pablo Ge, Rongbin Gong, Edward Strle, Klemen Sullivan, Maryrose P. Adam, Rosalyn M. White, Morris F. Olumi, Aria F. Diabetes Complications Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions (double knockout [DKO]), which develops type 2 diabetes. Bladders of DKO animals exhibited detrusor overactivity at an early stage: increased frequency of nonvoiding contractions during bladder filling, decreased voided volume, and dispersed urine spot patterns. In contrast, older animals with diabetes exhibited detrusor hypoactivity, findings consistent with clinical features of diabetes in humans. The tumor necrosis factor (TNF) superfamily genes were upregulated in DKO bladders. In particular, TNF-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α augmented the contraction of primary cultured bladder smooth muscle cells through upregulating Rho kinase activity and phosphorylating myosin light chain. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of Rho A signaling and reversed the bladder dysfunction, without affecting hyperglycemia. TNFRI combined with the antidiabetic agent, metformin, improved DBD beyond that achieved with metformin alone, suggesting that therapies targeting TNF-α may have utility in reversing the secondary urologic complications of type 2 diabetes. American Diabetes Association 2012-08 2012-07-17 /pmc/articles/PMC3402324/ /pubmed/22688336 http://dx.doi.org/10.2337/db11-1763 Text en © 2012 by the American Diabetes Association. https://creativecommons.org/licenses/by-nc-nd/3.0/Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ (https://creativecommons.org/licenses/by-nc-nd/3.0/) for details.
spellingShingle Complications
Wang, Zongwei
Cheng, Zhiyong
Cristofaro, Vivian
Li, Jijun
Xiao, Xingyuan
Gomez, Pablo
Ge, Rongbin
Gong, Edward
Strle, Klemen
Sullivan, Maryrose P.
Adam, Rosalyn M.
White, Morris F.
Olumi, Aria F.
Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title_full Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title_fullStr Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title_full_unstemmed Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title_short Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes
title_sort inhibition of tnf-α improves the bladder dysfunction that is associated with type 2 diabetes
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402324/
https://www.ncbi.nlm.nih.gov/pubmed/22688336
http://dx.doi.org/10.2337/db11-1763
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