Download PDF
Horm Metab Res 2016; 48(06): 404-412
DOI: 10.1055/s-0042-101549
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Effect of Telmisartan or Insulin on the Expression of Adiponectin and its Receptors in the Testis of Streptozotocin-Induced Diabetic Rats

Z. Guo
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
,
X. Yan
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
,
L. Wang
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
,
J. Wu
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
,
X. Jing
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
,
J. Liu
1   Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P. R. China
› Author Affiliations
Further Information

Publication History

received 02 November 2015

accepted 14 January 2016

Publication Date:
05 February 2016 (online)

Also available at
    Permissions and Reprints

Abstract

This study investigated the effect of insulin and telmisartan on the expression of adiponectin and its receptors, oxidative stress, and inflammatory cytokines in the testis of streptozotocin-induced diabetic rats. Male Wistar rats were randomly divided into control (C, n=8), diabetic (D, n=8), diabetic treated with insulin (DI, n=8), and diabetic treated with telmisartan (DT, n=8). Diabetic was induced by the peritoneal injection of a single dose of streptozotocin. Eight weeks later, bilateral testes were immediately removed after the rat was sacrificed. Epididymis was harvested to prepare sperm suspension. Plasma adiponectin, testicular interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA). The mRNA or protein expression of testicular adiponectin receptor 1 (adipoR1) and 2 (adipoR2), p22phox, transcription factor NF-E2 associated factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), AMPK-α, Akt, and eNOS was assayed by real-time fluorescence quantitative PCR or Western blot. There were significant pathological changes in the testes of diabetic rats. The levels of testicular weight, sperm number and motility, serum and testicular testosterone, plasma insulin and adiponectin, testicular adiponectin and its receptor 1, Nrf2, NQO1, HO-1, and phosphorylated-AMPK were significantly decreased in diabetic rats. The levels of blood glucose and lipids, and the levels of testicular p22phox, IL-6, TNF-α, phosphorylated-AKT, e-NOS, and nitric oxide (NO) were significantly increased in diabetic rats. These changes could be significantly reversed by insulin treatment. Similar results were observed with telmisartan treatment except for NQO1 mRNA and phosphorylated-AMPK. There was no significant difference in the expression of testicular adiponectin receptor 2 among 4 groups. The decreased adiponectin and its receptors, and the increased oxidative stress and inflammatory cytokines may play an important role in the testopathy of type 1 diabetic rats. Insulin and telmisartan may produce the protective effect on the testes of diabetic rats by upregulating the expression of adiponectin and its receptors and downregulating the level of oxidative stress and inflammatory cytokines.

Key words

adiponectin - adiponectin receptors - testes - insulin - telmisartan - oxidative stress - inflammatory cytokines

Supporting Information

 

  • References

  • 1 Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 2008; 4: 46-54
    CrossrefPubMedGoogle Scholar
  • 2 Mulholland J, Mallidis C, Agbaje I, McClure N. Male diabetes mellitus and assisted reproduction treatment outcome. Reprod Biomed Online 2011; 22: 215-219
    CrossrefPubMedGoogle Scholar
  • 3 Li M, Liu Z, Zhuan L, Wang T, Guo S, Wang S, Liu J, Ye Z. Effects of apocynin on oxidative stress and expression of apoptosis-related genes in testes of diabetic rats. Mol Med Rep 2013; 7: 47-52
    PubMedGoogle Scholar
  • 4 Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, Shan Z, Liu J, Tian H, Ji Q, Zhu D, Ge J, Lin L, Chen L, Guo X, Zhao Z, Li Q, Zhou Z, Shan G, He J. China National Diabetes and Metabolic Disorders Study Group. Prevalence of diabetes among men and women in China. N Engl J Med 2010; 362: 1090-1101
    CrossrefPubMedGoogle Scholar
  • 5 Mammi C, Calanchini M, Antelmi A, Cinti F, Rosano GM, Lenzi A, Caprio M, Fabbri A. Androgens and adipose tissue in males: a complex and reciprocal interplay. Int J Endocrinol 2012; 789653
    PubMedGoogle Scholar
  • 6 Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2004; 423: 762-769
    PubMedGoogle Scholar
  • 7 Ocón-Grove OM, Krzysik-Walker SM, Maddineni SR, Hendricks 3rd GL, Ramachandran R. Adiponectin and its receptors are expressed in the chicken testis: influence of sexual maturation on testicular ADIPOR1 and ADIPOR2 mRNA abundance. Reproduction 2008; 136: 627-638
    CrossrefPubMedGoogle Scholar
  • 8 Caminos JE, Nogueiras R, Gaytán F, Pineda R, González CR, Barreiro ML, Castaño JP, Malagón MM, Pinilla L, Toppari J, Diéguez C, Tena-Sempere M. Novel expression and direct effects of adiponectin in the rat testis. Endocrinology 2008; 149: 3390-3402
    CrossrefPubMedGoogle Scholar
  • 9 Martin LJ. Implications of adiponectin in linking metabolism to testicular function. Endocrine 2014; 46: 16-28
    CrossrefPubMedGoogle Scholar
  • 10 Pfaehler A, Nanjappa MK, Coleman ES, Mansour M, Wanders D, Plaisance EP, Judd RL, Akingbemi BT. Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis. Toxicol Lett 2012; 209: 78-85
    CrossrefPubMedGoogle Scholar
  • 11 Xu M, Dai DZ, Zhang Q, Cheng YS, Dai Y. Upregulated NADPH oxidase contributes to diabetic testicular complication and is relieved by strontium fructose 1,6-diphosphate. Exp Clin Endocrinol Diabetes 2010; 118: 459-465
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Wang Y, Zhang Z, Guo W, Sun W, Miao X, Wu H, Cong X, Wintergerst KA, Kong X, Cai L. Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. Am J Physiol Endocrinol Metab 2014; 307: E14-E23
    CrossrefPubMedGoogle Scholar
  • 13 Fouad AA, Jresat I. Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats. Fundam Clin pharmacol 2013; 27: 152-160
    CrossrefPubMedGoogle Scholar
  • 14 Kushwaha S, Jena GB. Telmisartan ameliorates germ cell toxicity in the STZ-induced diabetic rat: Studies on possible molecular mechanisms. Mutat Res 2013; 755: 11-23
    CrossrefPubMedGoogle Scholar
  • 15 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
    CrossrefPubMedGoogle Scholar
  • 16 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time PCR and the 2(Delta Delta C(T) method. Methods 2001; 25: 402-408
    CrossrefPubMedGoogle Scholar
  • 17 Rashid K, Sil PC. Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular stress-mediated mitochondria and endoplasmic reticulum-dependent apoptotic death. Biochim Biophys Acta 2015; 1852: 70-82
    CrossrefPubMedGoogle Scholar
  • 18 Schoeller EL, Albanna G, Frolova AI, Moley KH. Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes 2012; 61: 1869-1878
    CrossrefPubMedGoogle Scholar
  • 19 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288-1295
    CrossrefPubMedGoogle Scholar
  • 20 Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 2003; 52: 1355-1363
    CrossrefPubMedGoogle Scholar
  • 21 Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004; 279: 1304-1309
    CrossrefPubMedGoogle Scholar
  • 22 Luo XH, Guo LJ, Yuan LQ, Xie H, Zhou HD, Wu XP, Liao EY. Adiponectin stimulates human osteoblasts proliferation and differentiation via the MAPK signaling pathway. Exp Cell Res 2005; 309: 99-109
    CrossrefPubMedGoogle Scholar
  • 23 Rasul S, Ilhan A, Reiter MH, Baumgartner-Parzer S, Kautzky-Willer A. Relations of adiponectin to levels of metabolic parameters and sexual hormones in elderly type 2 diabetic patients. Gend Med 2011; 8: 93-102
    CrossrefPubMedGoogle Scholar
  • 24 Dupont J, Chabrolle C, Ramé C, Tosca L, Coyral-Castel S. Role of the peroxisome proliferator-activated receptors, adenosine monophosphate-activated kinase, and adiponectin in the ovary. PPAR Res. 2008; 176275
    PubMedGoogle Scholar
  • 25 Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CcCc, Itani SI, Lodish HF, Ruderman NB. Ehanced muscle fat oxidation and glucose transport by ACRP30 globular domain:Acetyl-CoA carboxylase inhibitation and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 2002; 99: 16309-16313
    CrossrefPubMedGoogle Scholar
  • 26 Chabrolle C, Jeanpierre E, Tosca L, Ramé C, Dupont J. Effects of high levels of glucose on the steroidogenesis and the expression of adiponectin receptors in rat ovarian cells. Reprod Biol Endocrinol 2008; 6: 11
    CrossrefPubMedGoogle Scholar
  • 27 Wu L, Xu B, Fan W, Zhu X, Wang G, Zhang A. Adiponectin protects leydig cells against proinflammatory cytokines by suppressing the nuclear factor-κB signaling pathway. FEBS J 2013; 280: 3920-3927
    CrossrefPubMedGoogle Scholar
  • 28 Roy S, Metya SK, Rahaman N, Sannigrahi S, Ahmed F. Ferulic acid in the treatment of post-diabetes testicular damage:relevance to the down regulation of apoptosis correlates antioxidant status via modulation of TGF-1β, IL-1β and Akt signalling. Cell Biochem Funct 2014; 32: 115-124
    CrossrefPubMedGoogle Scholar
  • 29 Zhao Y, Tan Y, Dai J, Wang B, Li B, Guo L, Cui J, Wang G, Li W, Cai L. Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis:essential roles of PTEN,PTP1B and TRB3. J Nutr Biochem 2012; 23: 1018-1026
    CrossrefPubMedGoogle Scholar
  • 30 Ribeiro DL, Góes RM, Pinto-Fochi ME, Taboga SR, Abrahamsson PA, Dizeyi N. AKT and AMPK activation after high-fat and high-glucose in vitro treatment of prostate epithelial cells. Horm Metab Res 2014; 46: 471-476
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Ducsay CA, Myers DA. eNOS activation and NO function: differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia. J Endocrinol 2011; 210: 259-269
    CrossrefPubMedGoogle Scholar
  • 32 Lee NP, Cheng CY. Nitric oxide and cyclic nucleotides: their roles in junction dynamics and spermatogenesis. Oxid Med Cell Longev 2008; 1: 25-32
    CrossrefPubMedGoogle Scholar
  • 33 Aksoy H, Aksoy Y, Ozbey I, Altuntas I, Akçay F. The relationship between varicocele and semen nitric oxide. Urol Res 2000; 28: 357-359
    CrossrefPubMedGoogle Scholar
  • 34 Lee NP, Cheng CY. Nitric oxide/nitric oxide synthase, spermatogenesis, and tight junction dynamics. Biol Reprod 2004; 70: 267-276
    CrossrefPubMedGoogle Scholar
  • 35 Zini A, O’Bryan MK, Magid MS, Schlegel PN. Immunohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death. Biol Reprod 1996; 55: 935-941
    CrossrefPubMedGoogle Scholar
  • 36 Hu Q, Chen J, Jiang C, Liu HF. Effect of peroxisome proliferator-activated receptor gamma agonist on heart of rabbits with acute myocardial ischemia/reperfusion injury. Asian Pac J Trop Med 2014; 7: 271-275
    CrossrefPubMedGoogle Scholar
  • 37 Lim CS, Vaziri ND. The effects of iron dextran on the oxidative stress in cardiovascular tissues of rats with chronic renal failure. Kidney Int 2004; 65: 1802-1809
    CrossrefPubMedGoogle Scholar
  • 38 Zhao Y, Tan Y, Dai J, Li B, Guo L, Cui J, Wang G, Shi X, Zhang X, Mellen N, Li W, Cai L. Exacerbation of diabetes-induced testicular apoptosis by zinc deficiency is most likely associated with oxidative stress, p38 MAPK activation, and p53 activation in mice. Toxicol Lett 2011; 200: 100-106
    CrossrefPubMedGoogle Scholar
  • 39 Li M, Liu Z, Zhuan L, Wang T, Guo S, Wang S, Liu J, Ye Z. Effects of apocynin on oxidative stress and expression of apoptosis-related genes in testes of diabetic rats. Mol Med Rep 2013; 7: 47-52
    PubMedGoogle Scholar
  • 40 Ashabi G, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis 2015; 30: 747-754
    CrossrefPubMedGoogle Scholar
  • 41 Lee J, Kim S. Upregulation of heme oxygenase-1 expression by dehydrodiconiferyl alcohol (DHCA) through the AMPK-Nrf2 dependent pathway. Toxicol Appl Pharmacol 2014; 281: 87-100
    CrossrefPubMedGoogle Scholar
  • 42 Nepal S, Kim MJ, Subedi A, Lee ES, Yong CS, Kim JA, Kang W, Kwak MK, Arya DS, Park PH. Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction. Biochem Pharmacol 2012; 84: 974-983
    CrossrefPubMedGoogle Scholar
  • 43 Antonopoulos AS, Margaritis M, Coutinho P, Shirodaria C, Psarros C, Herdman L, Sanna F, De Silva R, Petrou M, Sayeed R, Krasopoulos G, Lee R, Digby J, Reilly S, Bakogiannis C, Tousoulis D, Kessler B, Casadei B, Channon KM, Antoniades C. Adiponectin as a link between type 2 diabetes mellitus and vascular NADPH-oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes 2015; 64: 2207-2219
    CrossrefPubMedGoogle Scholar
  • 44 Guo Z, Zhang R, Li J, Xu G. Effect of telmisartan on the expression of adiponectin receptors and nicotinamide adenine dinucleotide phosphate oxidase in the heart and aorta in type 2 diabetic rats. Cardiovasc Diabetol 2012; 11: 94
    CrossrefPubMedGoogle Scholar