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The influence of hyperglycemia on the remodeling of urethral connective tissue in pregnant rats

  • Gabriela Marini
    Correspondence
    Corresponding author at: Universidade do Sagrado Coração Pró Reitoria de Pesquisa e Pós Graduação, R. Irmã Arminda, 10–50 – Jardim Brasil, CEP 17011-160, Bauru, São Paulo, Brazil.
    Affiliations
    Universidade do Sagrado Coração (USC), Bauru, São Paulo, Brazil

    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Fernanda Piculo
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Giovana Vesentini
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Débora C. Damasceno
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Flávia K. Delella
    Affiliations
    UNESP - Univ Estadual Paulista, Institute of Biosciences, Department of Morphology, Botucatu, São Paulo, Brazil
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  • Iracema M.P. Calderon
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Firouz Daneshgari
    Affiliations
    Case Western Reserve University, Department of Urology, Cleveland, OH, USA
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  • Sérgio L. Felisbino
    Affiliations
    UNESP - Univ Estadual Paulista, Institute of Biosciences, Department of Morphology, Botucatu, São Paulo, Brazil
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  • Angélica M.P. Barbosa
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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  • Marilza V.C. Rudge
    Affiliations
    UNESP - Univ Estadual Paulista, Botucatu Medical School, Department of Gynecology and Obstetrics, Laboratory of Experimental Research on Gynecology and Obstetrics, Botucatu, São Paulo, Brazil
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Published:December 16, 2017DOI:https://doi.org/10.1016/j.ejogrb.2017.12.032

      Abstract

      Objective

      To analyze the distribution and quantification of the key structural extracellular matrix components of the urethral tissue in a rat model of hyperglycemia and pregnancy.

      Study design

      A total of 120 female Wistar rats were distributed into the following four experimental groups: virgin, pregnant, hyperglycemic and hyperglycemic + pregnant groups. The urethra was harvested for histochemical, morphometric, immunohistochemical, Western blot and glycosaminoglycan analyses. All protocols were approved by the Institutional Animal Care and Use Committee of Botucatu Medical School (process number 828–2010).

      Results

      The hyperglycemic + pregnant group showed significantly increased stiffness in urethral tissue. The total striated muscle was decreased, with increased deposition of collagen fibers around the muscle fibers and a change in the organization of the collagen fibrils. An increase in the relative collagen type I/III ratio and a decrease in total glycosaminoglycans were also observed.

      Conclusions

      This study provides the first line of experimental evidence supporting a metabolic relationship between hyperglycemia and urethral remodeling of connective tissue in pregnant rats. The different organization of the collagen fibrils and the profile of glycosaminoglycans found in urethral samples suggest that the pathology of the urethral fibromuscular system could be related to hyperglycemia-induced pelvic floor dysfunction in women, which has direct clinical implications with the possibility to develop new multidisciplinary treatments for improving the health care of these women.

      Keywords

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      References

        • Guariguata L.
        • Whiting D.R.
        • Hambleton I.
        • Beagley J.
        • Linnenkamp U.
        • Shaw J.E.
        Global estimates of diabetes prevalence for 2013 and projections for 2035.
        Diabetes Res Clin Pract. 2014; 103: 137-149
        • Wu J.M.
        • Vaughan C.P.
        • Goode P.S.
        • Redden D.T.
        • Burgio K.L.
        • Richter H.E.
        • et al.
        Prevalence and trends of symptomatic pelvic floor disorders in U.S. women.
        Obstet Gynecol. 2014; 123: 141-148
        • Lenherr S.M.
        • Clemens J.Q.
        • Braffett B.H.
        • Dunn R.L.
        • Cleary P.A.
        • Kim C.
        • et al.
        Glycaemic control and risk of incident urinary incontinence in women with type 1 diabetes: results from the diabetes control and complications trial and epidemiology of diabetes interventions and complications (DCCT/EDIC) study.
        Diabet Med. 2016; 33: 1528-1535
        • Sangsawang B.
        Risk factors for the development of stress urinary incontinence during pregnancy in primigravidae: a review of the literature.
        Eur J Obstet Gynecol Reprod Biol. 2014; 178: 27-34
        • Jimenez-Rodriguez J.
        • Carbajal-Ramirez A.
        • Meza-Vazquez H.
        • Moreno-Palacios J.
        • Serrano-Brambila E.
        Prevalence of urinary tract symptoms in women with diabetes mellitus.
        Rev Med Inst Mex Seguro Soc. 2016; 54: 70-74
        • Wang R.
        • Lefevre R.
        • Hacker M.R.
        • Golen T.H.
        Diabetes, glycemic control, and urinary incontinence in women.
        Female Pelvic Med Reconstr Surg. 2015; 21: 293-297
        • Isik H.
        • Aynioglu O.
        • Sahbaz A.
        • Selimoglu R.
        • Timur H.
        • Harma M.
        Are hypertension and diabetes mellitus risk factors for pelvic organ prolapse?.
        Eur J Obstet Gynecol Reprod Biol. 2016; 197: 59-62
        • Barbosa A.M.
        • Dias A.
        • Marini G.
        • Calderon I.M.
        • Witkin S.
        • Rudge M.V.
        Urinary incontinence and vaginal squeeze pressure two years post-cesarean delivery in primiparous women with previous gestational diabetes mellitus.
        Clinics. 2011; 66: 1341-1346
        • Chuang C.M.
        • Lin I.F.
        • Horng H.C.
        • Hsiao Y.H.
        • Shyu I.L.
        • Chou P.
        The impact of gestational diabetes mellitus on postpartum urinary incontinence: a longitudinal cohort study on singleton pregnancies.
        BJOG. 2012; 119: 1334-1343
        • Morgan D.M.
        • Umek W.
        • Guire K.
        • Morgan H.K.
        • Garabrant A.
        • DeLancey J.O.
        Urethral sphincter morphology and function with and without stress incontinence.
        J Urol. 2009; 182: 203-209
        • DeLancey J.O.
        • Trowbridge E.R.
        • Miller J.M.
        • Morgan D.M.
        • Guire K.
        • Fenner D.E.
        • et al.
        Stress urinary incontinence: relative importance of urethral support and urethral closure pressure.
        J Urol. 2008; 179: 2286-2290
        • Fitzgerald M.P.
        • Mollenhauer J.
        • Hale D.S.
        • Benson J.T.
        • Brubaker L.
        Urethral collagen morphologic characteristics among women with genuine stress incontinence.
        Am J Obstet Gynecol. 2000; 182: 1565-1574
        • Feldner Jr., P.C.
        • Sartori M.G.
        • Nader H.B.
        • Dietrich C.P.
        • Rodrigues de Lima G.
        • Baracat E.C.
        • et al.
        Sulfated glycosaminoglycans of periurethral tissue in pre- and postmenopausal women.
        Eur J Obstet Gynecol Reprod Biol. 2008; 139: 252-255
        • Eckes B.
        • Zigrino P.
        • Kessler D.
        • Holtkotter O.
        • Shephard P.
        • Mauch C.
        • et al.
        Fibroblast-matrix interactions in wound healing and fibrosis.
        Matrix Biol. 2000; 19: 325-332
        • Liapis A.
        • Bakas P.
        • Pafiti A.
        • Frangos-Plemenos M.
        • Arnoyannaki N.
        • Creatsas G.
        Changes of collagen type III in female patients with genuine stress incontinence and pelvic floor prolapse.
        Eur J Obstet Gynecol Reprod Biol. 2001; 97: 76-79
        • Feldner Jr., P.C.
        • Kati L.M.
        • Sartori M.G.
        • Baracat E.C.
        • Rodrigues de Lima G.
        • Nader H.B.
        • et al.
        Sulfated glycosaminoglycans of the periurethral tissue in women with and without stress urinary incontinence, according to genital prolapse stage.
        Eur J Obstet Gynecol Reprod Biol. 2006; 126: 250-254
        • Chen H.Y.
        • Lin Y.N.
        • Chen Y.H.
        • Chen W.C.
        Stress urinary incontinence following vaginal trauma involves remodeling of urethral connective tissue in female mice.
        Eur J Obstet Gynecol Reprod Biol. 2012; 163: 224-229
        • Duran-Jimenez B.
        • Dobler D.
        • Moffatt S.
        • Rabbani N.
        • Streuli C.H.
        • Thornalley P.J.
        • et al.
        Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes.
        Diabetes. 2009; 58: 2893-2903
        • Campeau L.
        • Gorbachinsky I.
        • Badlani G.H.
        • Andersson K.E.
        Pelvic floor disorders: linking genetic risk factors to biochemical changes.
        BJU Int. 2011; 108: 1240-1247
        • Alperin M.
        • Kaddis T.
        • Pichika R.
        • Esparza M.C.
        • Lieber R.L.
        Pregnancy-induced adaptations in intramuscular extracellular matrix of rat pelvic floor muscles.
        Am J Obstet Gynecol. 2016; 215 (210 e1-7)
        • Zhang X.
        • Alwaal A.
        • Lin G.
        • Li H.
        • Zaid U.Z.
        • Wang G.
        • et al.
        Urethral musculature and innervation in the female rat.
        Neurourol Urodyn. 2016; 35: 382-389
        • Marini G.
        • Barbosa A.M.
        • Damasceno D.
        • Matheus S.M.M.
        • Castro R.A.
        • Girão M.J.B.C.
        • et al.
        Morphological changes in the fast vs slow fiber profiles of the urethras of diabetic pregnant rats.
        Urogynaecologia. 2011; 25 (e9:31-6)
        • Piculo F.
        • Marini G.
        • Barbosa A.M.
        • Damasceno D.C.
        • Matheus S.M.
        • Felisbino S.L.
        • et al.
        Urethral striated muscle and extracellular matrix morphological characteristics among mildly diabetic pregnant rats: translational approach.
        Int Urogynecol J. 2014; 25: 403-415
        • Marini G.
        • Piculo F.
        • Vesentini G.
        • Barbosa A.M.
        • Damasceno D.C.
        • Matheus S.M.
        • et al.
        Effects of short-term severe and long-term mild STZ-induced diabetes in urethral tissue of female rats.
        Neurourol Urodyn. 2016; 36: 574-579
        • Falconer C.
        • Blomgren B.
        • Johansson O.
        • Ulmsten U.
        • Malmstrom A.
        • Westergren-Thorsson G.
        • et al.
        Different organization of collagen fibrils in stress-incontinent women of fertile age.
        Acta Obstet Gynecol Scand. 1998; 77: 87-94
        • Rodrigues Jr., A.A.
        • Suaid H.J.
        • Fazan V.P.
        • Reis R.B.
        • Cologna A.J.
        • Tucci Jr., S.
        • et al.
        Histologic study of urethral extracellular matrix and collagen from aging and long-term alloxan-induced diabetic male rats.
        Urology. 2011; 77 (510 e6-11)
        • Tibbs M.K.
        Wound healing following radiation therapy: a review.
        Radiother Oncol. 1997; 42: 99-106
        • Liberman D.
        • Mehus B.
        • Elliott S.P.
        Urinary adverse effects of pelvic radiotherapy.
        Transl Androl Urol. 2014; 3: 186-195
        • Gharaee-Kermani M.
        • Rodriguez-Nieves J.A.
        • Mehra R.
        • Vezina C.A.
        • Sarma A.V.
        • Macoska J.A.
        Obesity-induced diabetes and lower urinary tract fibrosis promote urinary voiding dysfunction in a mouse model.
        Prostate. 2013; 73: 1123-1133
        • Jia G.
        • Aroor A.R.
        • DeMarco V.G.
        • Martinez-Lemus L.A.
        • Meininger G.A.
        • Sowers J.R.
        Vascular stiffness in insulin resistance and obesity.
        Front Physiol. 2015; 6: 231
        • Berria R.
        • Wang L.
        • Richardson D.K.
        • Finlayson J.
        • Belfort R.
        • Pratipanawatr T.
        • et al.
        Increased collagen content in insulin-resistant skeletal muscle.
        Am J Physiol Endocrinol Metab. 2006; 290: E560-E565
        • Kim J.H.
        • Huang X.
        • Liu G.
        • Moore C.
        • Bena J.
        • Damaser M.S.
        • et al.
        Diabetes slows the recovery from urinary incontinence due to simulated childbirth in female rats.
        Am J Physiol Regul Integr Comp Physiol. 2007; 293: R950-5
        • Wu L.
        • Zhang X.
        • Xiao N.
        • Huang Y.
        • Kavran M.
        • Elrashidy R.A.
        • et al.
        Functional and morphological alterations of the urinary bladder in type 2 diabetic FVB(db/db) mice.
        J Diabetes Complicat. 2016; 30: 778-785
        • Elrashidy R.
        • Xu Z.
        • Daneshgari G.
        • Liu G.
        MP 31-14 imbalance between matrix etalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) contributes to increased fibrosis of bladder in long-term diabetic rats.
        J Urol. 2017; 197: e404
        • Hiebert L.M.
        • Han J.
        • Mandal A.K.
        Glycosaminoglycans, hyperglycemia, and disease.
        Antioxid Redox Signal. 2014; 21: 1032-1043
        • Gautieri A.
        • Redaelli A.
        • Buehler M.J.
        • Vesentini S.
        Age- and diabetes-related nonenzymatic crosslinks in collagen fibrils: candidate amino acids involved in advanced glycation end-products.
        Matrix Biol. 2014; 34: 89-95
        • Li Y.
        • Fessel G.
        • Georgiadis M.
        • Snedeker J.G.
        Advanced glycation end-products diminish tendon collagen fiber sliding.
        Matrix Biol. 2013; 32: 169-177
        • Kolset S.O.
        • Reinholt F.P.
        • Jenssen T.
        Diabetic nephropathy and extracellular matrix.
        J Histochem Cytochem. 2012; 60: 976-986
        • Knuuti E.
        • Kauppila S.
        • Kotila V.
        • Risteli J.
        • Nissi R.
        Genitourinary prolapse and joint hypermobility are associated with altered type I and III collagen metabolism.
        Arch Gynecol Obstet. 2011; 283: 1081-1085