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Fibrosis in the Urinary Bladder caused by Diabetes Mellitus Type II Student: Nadia Tsado Mentors: Matthew H. Ho, M.D., Ph.D., Gaby Nolazco, M. Sc. Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles Drew University of Medicine and Science, Los Angeles, California. HYPOTHESIS MATERIALS AND METHODS RESULTS CONCLUSION I would like to thank Dr. Matthew Ho and Gaby Nolazco of the Charles Drew research endocrinology Department. Dr. Donzalez- Cadavid has also contributed to make this project possible with the feedback he has given to this project. I thank the NIH/Step Up Program, Dee Flemming and Emma Taylor for giving me an opportunity to do research in the lab for two consecutive summers. The hypothesis of this study is that diabetes Mellitus Type II causes urinary bladder disorders as a result of an over production of fibrosis and a decrease in smooth muscle cells in the detrusor. BACKGROUND Diabetes affects the bladder causing smooth muscle tissue reduction as well as an increase of collagen accumulation and fibrosis, thus the bladder is not able to function properly. Type II diabetes, in both humans and rat, is also associated with loss of smooth muscle (SM) tissue within the bladder together with an increase in fibrosis, arterial stiffness and increased oxidative stress. The concept that a progressive fibrosis of the SM tissue within the bladder is responsible for bladder disorder associated with diabetes, aging, heavy smoking, with that said pelvic surgery has become more of interest. The detrusor is the wall of the bladder that is made up of smooth musclet is responsible for removing urine from the bladder. There have been numerous studies on other organs that have been affected by type II diabetes, which can lead to an increase in collagen and an decrease in smooth muscle. The detrusor (smooth muscle of the bladder) is unable to function because of the increase of collagen which leads to an increase of fibrosis in the urinary bladder. The animals consisted of four groups (eight animals per group); non-diabetic, (lean Zucker fa/fa rat, LZFR), diabetic treated with Molsidomine, an NO donor, Allopurinol, a drug used to treat high uric acid in the blood that causes insulin resistance, and type II diabetic mellitus (Zucker diabetic fa/fa rat, ZDFR). Animal bladders were extracted and subjected to paraffin-wax embedding. Paraffin embedded tissue sections endured immunohistochemistry techniques such as: Masson trichrome, a procedure that stains the collagen/smooth muscle, Hematoxylin Eosin which stains the cell membrane, and Picro Sirius red which stains collagen type1 and collagen III. The total reduction of the smooth muscle cells (SMC)/collagen ratio was confirmed by quantitative image analysis (QIA). The ratio of type I collagen to type III collagen was also confirmed by QIA. There was a significant increase of collagen in the urinary bladder of type II DM more so than the non-DM group. As a result of the increase in collagen in the diabetic and diabetic treated group there is a decrease in smooth muscle The collagen III/I decreased in the diabetic and treated bladders. As a result the data shows that type II DM can cause an increase in both fibrosis and smooth muscle cells turnover in the urinary bladder, which may subsequently cause urinary bladder disorders. Fibrosis occurs over time in a bladder affected by type II DM. This overproduction of fibrosis can cause neuropathy and stress urinary incontinence (SUI. ) in the bladder as the type II DM continues to affect the bladder Picro Sirius Red 20x LZDFR ZDFR Masson Trichome 20x Results ZDF mol ZDF allo Hematoxyl in &Eosin 10x REFERENCES 1. Kovanecz I, Nolazco G, Ferrini MG, et al. Early onset of fibrosis within the arterial media in a rat model of type 2 diabetes mellitus within erectile dysfunction. BJU International. 2008;103:1396-1404 2. Kebapc N, Yenimez A, Efe B, Entok E,Demirustu C. Bladder dysfunction in type 2 diabetic patients. 2007;26:814-819 ACKNOWLEDGEMENTS AIM The aim of this study is to determine whether diabetes mellitus type II affects the smooth muscle to collagen ratio, which together with TGF- beta is the marker of fibrosis, in the urinary bladder. Another aim is to verify whether diabetes mellitus type II affects the type I and III collagen ratio.
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Fibrosis in the Urinary Bladder caused by Diabetes Mellitus Type II Student: Nadia Tsado
Mentors: Matthew H. Ho, M.D., Ph.D., Gaby Nolazco, M. Sc.Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles Drew University of
Medicine and Science, Los Angeles, California.
HYPOTHESIS
MATERIALS AND METHODS
RESULTS
CONCLUSION
I would like to thank Dr. Matthew Ho and Gaby Nolazco of the Charles Drew research endocrinology Department. Dr. Donzalez- Cadavid has also contributed to make this project possible with the feedback he has given to this project. I thank the NIH/Step Up Program, Dee Flemming and Emma Taylor for giving me an opportunity to do research in the lab for two consecutive summers.
The hypothesis of this study is that diabetes Mellitus Type II causes urinary bladder disorders as a result of an over production of fibrosis and a decrease in smooth muscle cells in the detrusor.
BACKGROUND Diabetes affects the bladder causing smooth muscle tissue reduction as well as an increase of collagen accumulation and fibrosis, thus the bladder is not able to function properly. Type II diabetes, in both humans and rat, is also associated with loss of smooth muscle (SM) tissue within the bladder together with an increase in fibrosis, arterial stiffness and increased oxidative stress. The concept that a progressive fibrosis of the SM tissue within the bladder is responsible for bladder disorder associated with diabetes, aging, heavy smoking, with that said pelvic surgery has become more of interest. The detrusor is the wall of the bladder that is made up of smooth musclet is responsible for removing urine from the bladder. There have been numerous studies on other organs that have been affected by type II diabetes, which can lead to an increase in collagen and an decrease in smooth muscle. The detrusor (smooth muscle of the bladder) is unable to function because of the increase of collagen which leads to an increase of fibrosis in the urinary bladder.
The animals consisted of four groups (eight animals per group); non-diabetic, (lean Zucker fa/fa rat, LZFR), diabetic treated with Molsidomine, an NO donor, Allopurinol, a drug used to treat high uric acid in the blood that causes insulin resistance, and type II diabetic mellitus (Zucker diabetic fa/fa rat, ZDFR). Animal bladders were extracted and subjected to paraffin-wax embedding. Paraffin embedded tissue sections endured immunohistochemistry techniques such as: Masson trichrome, a procedure that stains the collagen/smooth muscle, Hematoxylin Eosin which stains the cell membrane, and Picro Sirius red which stains collagen type1 and collagen III. The total reduction of the smooth muscle cells (SMC)/collagen ratio was confirmed by quantitative image analysis (QIA). The ratio of type I collagen to type III collagen was also confirmed by QIA.
There was a significant increase of collagen in the urinary bladder of type II DM more so than the non-DM group. As a result of the increase in collagen in the diabetic and diabetic treated group there is a decrease in smooth muscle The collagen III/I decreased in the diabetic and treated bladders.
As a result the data shows that type II DM can cause an increase in both fibrosis and smooth muscle cells turnover in the urinary bladder, which may subsequently cause urinary bladder disorders. Fibrosis occurs over time in a bladder affected by type II DM. This overproduction of fibrosis can cause neuropathy and stress urinary incontinence (SUI. ) in the bladder as the type II DM continues to affect the bladder
Picro Sirius Red20x
LZDFR ZDFR
Masson Trichome20x
Results
ZDF mol
ZDF allo
Hematoxylin &Eosin10x
REFERENCES1. Kovanecz I, Nolazco G, Ferrini MG, et al. Early onset of fibrosis within the arterial media in a rat model of type 2 diabetes mellitus within erectile dysfunction. BJU International. 2008;103:1396-14042. Kebapc N, Yenimez A, Efe B, Entok E,Demirustu C. Bladder dysfunction in type 2 diabetic patients. 2007;26:814-819
ACKNOWLEDGEMENTS
AIM The aim of this study is to determine whether diabetes mellitus type II affects the smooth muscle to collagen ratio, which together with TGF- beta is the marker of fibrosis, in the urinary bladder. Another aim is to verify whether diabetes mellitus type II affects the type I and III collagen ratio.
