Upregulated NADPH Oxidase Contributes to Diabetic Testicular Complication and is Relieved by Strontium Fructose 1,6-Diphosphate

Abstract

Diabetes is frequently associated with declining sexual function resulting from oxidative damage. NADPH oxidase is a major resource of reactive oxygen species (ROS) in the testes and is likely related to an activated endothelin-1 (ET-1) system. An activation of NADPH oxidase - ET-1 pathway was hypothesized in diabetic testopathy. We verified the hypothesis and tested if strontium fructose 1,6-diphosphate (FDP-Sr) could relieve these changes in diabetic testis as compared to testosterone propionate (TP) and sildenafil. Diabetes was produced in male Sprague-Dawley rats 8 weeks after a single injection of streptozotocin (STZ), and interventions with testosterone propionate (TP), sildenafil and FDP-Sr were conducted in the last 4 weeks. Blood glucose, testosterone, follicle stimulating hormone (FSH) , luteinizing hormone (LH) and expressions of NADPH oxidase subunits and the ET system were measured. Decreased insulin, FSH, LH and testosterone in serum were found associating with testicular oxidative stress in STZ-injected rats. Additionally, over-expressions of NADPH oxidase p22, p47, p67 subunits and the ET pathway were significant in the diabetic testis relative to normal and were completely abolished by FDP-Sr. Both TP and sildenafil were not beneficial to diabetic testopathy except serum androgen raised by TP. Activated NADPH oxidase and ET system are significant contributing to testis injury and are responded to FDP-Sr only, against both TP and sildenafil, by restoring the testis function and the hypothalamus-pituitary-testis axis. It is due to its extra-energy supply and an antioxidant activity of FDP-Sr.

NADPH oxidase - ET-1 FDP-Sr - diabetes - testicular dysfunction

References

• 1 Abdul-Ghani MA, Jani R, Chavez A. et al . Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants.  Diabetologia. 2009;  52 574-582
• 2 Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach.  Br J Urol Int. 2005;  95 503-507
• 3 Baker MA, Aitken RJ. The importance of redox regulated pathways in sperm cell biology.  Mol Cell Endocrinol. 2004;  216 47-54
• 4 Ballester J, Muñoz MC, Domínguez J. et al . Insulin-dependent diabetes affects testicular function by FSH- and LH-linked mechanisms.  J Androl. 2004;  25 706-719
• 5 Beg S, Al-Khoury L, Cunningham GR. Testosterone replacement in men.  Curr Opin Endocrinol Diabetes Obes. 2008;  15 364-370
• 6 Chen HC, Guh JY, Shin SJ. et al . Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo.  J. Lab. Clin. Med. 2000;  135 309-315
• 7 Cheng YS, Dai DZ, Ji H. et al . Testis dysfunction by isoproterenol is mediated by upregulating endothelin receptor A, leptin and protein kinase C ε and is attenuated by an endothelin receptor antagonist CPU0213.  Reprod Toxic. Revised.
• 8 Cocuzza M, Sikka SC, Athayde KS. et al . Clinical relevance of oxidative stress and sperm chromatin damage in male infertility: An evidence based analysis.  Int Braz J Urol. 2007;  33 603-621
• 9 Díaz-Ruiz R, Avéret N, Araiza D. et al . Mitochondrial oxidative phosphorylation is regulated by fructose 1,6-bisphosphate. A possible role in Crabtree effect induction?.  Biol Chem. 2008;  283 26948-26955
• 10 Feng Y, Zhang Q, Dai DZ. et al . Strontium fructose 1,6-diphosphate rescues adenine-induced male hypogonadism and upregulates the testicular endothelin-1 system.  Clin Exp Pharmacol Physiol. 2007;  34 1131-1137
• 11 Fonseca SG, Burcin M, Gromada J. et al . Endoplasmic reticulum stress in beta-cells and development of diabetes.  Curr Opin Pharmacol. 2009;  9 763-770
• 12 Ford WC. Regulation of sperm function by reactive oxygen species.  Hum Reprod Update. 2004;  10 387-399
• 13 Geiszt M, Lekstrom K, Leto TL. Analysis of mRNA transcripts from the NAD(P)H oxidase 1 (Nox1) gene. Evidence against production of the NADPH oxidase homolog-1 short (NOH-1S) transcript variant.  J Biol Chem. 2004;  279 51661-51668
• 14 Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.  Nat Rev Drug Discov. 2006;  5 689-702
• 15 Hatzimouratidis K. Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence.  Clin Interv Aging. 2006;  1 403-414
• 16 Huhtaniemi I, Alevizaki M. Mutations along the hypothalamic-pituitary-gonadal axis affecting male reproduction.  Reprod Biomed Online. 2007;  15 622-632
• 17 Koupparis AJ, Jeremy JY, Muzaffar S. et al . Sildenafil inhibits the formation of superoxide and the expression of gp47 NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells.  BJU Int. 2005;  96 423-427
• 18 Kumanov P, Tomova A, Kirilov G. et al . Increased plasma endothelin levels in patients with male hypogonadism.  Andrologia. 2002;  34 29-33
• 19 Kumanov P, Tomova A, Kirilov G. Testosterone replacement therapy in male hypogonadism is not associated with increase of endothelin-1 levels.  Int J Androl. 2007;  30 41-47
• 20 Mancini A, Leone E, Festa R. et al . Effects of testosterone on antioxidant systems in male secondary hypogonadism.  J Androl. 2008;  29 622-629
• 21 Na T, Dai DZ, Tang XY. et al . Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017.  Naunyn Schmiedebergs Arch Pharmacol. 2007;  375 39-49
• 22 O'Flaherty C, de Lamirande E, Gagnon C. Positive role of reactive oxygen species in mammalian sperm capacitation: triggering and modulation of phosphorylation events.  Free Radic Biol Med. 2006;  41 528-540
• 23 Pitteloud N, Hardin M, Dwyer AA. et al . Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men.  J Clin Endocrinol Metab. 2005;  90 2636-2641
• 24 Pongratz RL, Kibbey RG, Kirkpatrick CL. et al . Mitochondrial dysfunction contributes to impaired insulin secretion in INS-1 cells with dominant-negative mutations of HNF-1alpha and in HNF-1alpha-deficient islets.  J Biol Chem. 2009;  284 16808-16821
• 25 Rabijewski M, Zgliczyñski W. Pathogenesis, evaluation and treatment of hypogonadism in men.  Endokrynol Pol. 2009;  60 222-233 [Article in Polish]
• 26 Raynaud JP. Testosterone deficiency syndrome: treatment and cancer risk.  J Steroid Biochem Mol Biol. 2009;  114 96-105
• 27 Rivlin J, Mendel J, Rubinstein S. et al . Role of hydrogen peroxide in sperm capacitation and acrosome reaction.  Biol Reprod. 2004;  70 518-522
• 28 Romanelli F, Fillo S, Isidori A. et al . Stimulatory action of endothelin-1 on rat Leydig cells: involvement of endothelin-A subtype receptor and phospholipase A2-arachidonate metabolism system.  Life Sci. 1997;  61 557-566
• 29 Sabeur K, Ball BA. Characterization of NADPH oxidase 5 in equine testis and spermatozoa.  Reproduction. 2007;  134 263-270
• 30 Santiemma V, Rossi F, Guerrini L. et al . Adrenomedullin inhibits the contraction of cultured rat testicular peritubular myoid cells induced by endothelin-1.  Biol Reprod. 2001;  64 619-624
• 31 Scarano WP, Messias AG, Oliva SU. et al . Effect of Melatonin on Testicular Damage in Streptozotocin-Induced Diabetes Rats.  Int J Androl. 2006;  29 482-488
• 32 Sofikitis N, Giotitsas N, Tsounapi P. et al . Hormonal regulation of spermatogenesis and spermiogenesis.  J Steroid Biochem Mol Biol. 2008;  109 323-330
• 33 Sudha S, Valli G, Julie PM. et al . Influence of streptozotocin-induced diabetes and insulin treatment on the pituitary-testicular axis during sexual maturation in rats.  Exp Clin Endocrinol Diabetes. 2000;  108 14-20
• 34 Tang XY, Zhang Q, Dai DZ. et al . Effects of strontium fructose 1,6-diphosphate on expression of apoptosis-related genes and oxidative stress in testes of diabetic rats.  Int J Urol. 2008;  15 251-256
• 35 Wilkins MR, Wharton J, Grimminger F. et al . Phosphodiesterase inhibitors for the treatment of pulmonary hypertension.  Eur Respir J. 2008;  32 198-209
• 36 Xu H, Duan J, Wang W. et al . Reactive oxygen species mediate oxidized low-density lipoprotein-induced endothelin-1 gene expression via extracellular signal-regulated kinase in vascular endothelial cells.  J Hypertens. 2008;  26 956-963
• 37 Xu M, Dai DZ, Dai Y. Normalizing NADPH oxidase contributes to attenuating diabetic nephropathy by the dual endothelin receptor antagonist CPU0213 in Rats.  Am J Nephrol. 2008;  29 252-256
• 38 Zeng Q, Zhou Q, Yao F. et al . Endothelin-1 regulates cardiac L-type calcium channels via NAD(P)H oxidase-derived superoxide.  J Pharmacol Exp Ther. 2008;  326 732-738

Correspondence