Impact of chronic renal failure and peritoneal dialysis fluids on advanced glycation end product and iNOS levels in penile tissue: an experimental study (original) (raw)
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American Journal of Nephrology, 2003
Chronic renal failure W Rat testis W Advanced glycation end products W Inducible nitric oxide synthase W Infertility Abstract Objectives: To investigate the impact of advanced glycation end products (AGEs) and inducible nitric oxide synthase (iNOS) in chronic renal failure (CRF)-associated testicular dysfunction in an experimental model. In additionally, we examined whether different peritoneal dialysis (PD) fluids could contribute to the elevation in AGE level and iNOS expression in the testes. Methods: Adult male Wistar rats, 10 and 12 weeks of age and weighing 200-330 g, were divided into 5 groups. Group 1 served as the control group. In group 2, CRF was induced and a peritoneal catheter was implanted, but the dialysis procedure was not performed until the end of the study. In group 3, CRF was induced and PD was performed with dialysis fluids containing 1.36% glucose and icodextrin. In group 4, CRF rats received dialysis fluids containing 3.86% glucose and icodextrin. Finally, an indwelling catheter was implanted and the dialysis procedure was performed using dialysis fluids containing 3.86% glucose and icodextrin (group 5). Chronic PD began 4 weeks after insertion of the catheter. Each morning, this fluid was drained and 20 ml dialysis fluid, containing either 1.36 or 3.86% glucose, was given intraperitoneally for 4 h in unanesthetized animals. Each evening, 20 ml icodextrin was given for 10 h. The dialysis procedure was performed for 8 weeks. The AGE level was determined from the 5-hydroxymethyl-2-furaldehyde (5-HMF) content of penis samples and iNOS expression was assessed by immunohistochemistry. Results: The elevation of 5-HMF was significant in the testes from groups 2, 3, 4, and 5 when compared with group 1. Furthermore, the differences between groups 2 and 4, 3 and 4, and 4 and 5 were also significant (p ! 0.05). Immunohistochemical analysis revealed the presence of iNOS predominantly in the Leydig cells. While iNOS staining was significantly lower in group 1 than in other groups, there were also significant differences between groups 2 and 3, 2 and 4, 2 and 5, 3 and 5, and 4 and 5 (p ! 0.05). Finally, a significant statistical correlation was found between the 5-HMF and iNOS levels (r = 0.698, p = 0.001). Conclusions: The present study identifies, for the first time, a potential role 362
Journal of Urology, 1999
Purpose: Patients with chronic renal failure experience a variety of physical and metabolic alterations. Uremia is often accompanied by erectile dysfunction (ED). Little information is available concerning the underlying pathophysiological mechanisms by which chronic renal failure can lead to erectile dysfunction. In this study, chronic renal failure was induced by 516 nephrectomy in a rat model. Cavernous nerve stimulation was used to measure the intracavernous pressure (ICP) rise.
Journal of Sexual Medicine, 2010
Introduction. Endogenously elicited inducible nitric oxide synthase (iNOS) induction counteracts fibrosis and oxidative stress in penile tissues in rat models of Peyronie's disease and erectile dysfunction.Aim. The current study aimed to determine whether the genetic blockade of iNOS expression in the iNOS knock out (iNOS KO) mouse intensifies fibrosis and oxidative stress in the penile corpora cavernosa, and this is exacerbated by streptozotocin (STZ)-induced diabetes and counteracted by insulin.Main Outcomes Measures. Quantitative assessment of histological and biochemical markers in mouse corporal tissue.Methods. Male iNOS KO and wild type (WT) mice were left untreated or injected with STZ, with or without insulin treatment. At 8 weeks, glycemia, glucosuria, and proteinuria were determined, and corporal tissue sections were obtained and subjected to Masson trichrome staining for smooth muscle (SM)/collagen ratio, and immunostaining for α-smooth muscle actin (ASMA) for, SM content, proliferating cell nuclear antigen (PCNA) for cell replication, TGFβ1 as profibrotic factor, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis, and xanthine oxidoreductase (XOR) for oxidative stress. Collagen was estimated by the hydroxyproline reaction.Results. The corporal SM/collagen ratio and SM content were reduced, and collagen content increased in iNOS KO mice as compared with WT mice, but apoptosis was decreased and cell replication increased, whereas TGFβ1 and XOR did not vary. Severe hyperglycemia caused in the WT a reduction of the corporal SM/collagen ratio and SM content and an increase in apoptosis without changes in PCNA, TGFβ1, or XOR. In the iNOS KO mouse the hyperglycemia-induced alterations were exacerbated, with additional increases in oxidative stress and TGFβ1. Insulin normalized glycemia and partially protected the SM in both the WT and the iNOS KO mice.Conclusions. The antifibrotic, antioxidative, and SM-protective roles of iNOS in the penile corpora cavernosa were confirmed in the iNOS KO/STZ mouse model. These findings support the importance of endogenously-elicited iNOS induction in protecting the penile corpora cavernosa from the pro-fibrotic effects of hyperglycemia. Ferrini MG, Rivera S, Moon J, Vernet D, Rajfer J, and Gonzalez-Cadavid NF. The genetic inactivation of inducible nitric oxide synthase (iNOS) intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes. J Sex Med 2010;7:3033–3044.
The Journal of Sexual Medicine, 2010
Endogenously elicited inducible nitric oxide synthase (iNOS) induction counteracts fibrosis and oxidative stress in penile tissues in rat models of Peyronie's disease and erectile dysfunction. Aim. The current study aimed to determine whether the genetic blockade of iNOS expression in the iNOS knock out (iNOS KO) mouse intensifies fibrosis and oxidative stress in the penile corpora cavernosa, and this is exacerbated by streptozotocin (STZ)-induced diabetes and counteracted by insulin. Main Outcomes Measures. Quantitative assessment of histological and biochemical markers in mouse corporal tissue. Methods. Male iNOS KO and wild type (WT) mice were left untreated or injected with STZ, with or without insulin treatment. At 8 weeks, glycemia, glucosuria, and proteinuria were determined, and corporal tissue sections were obtained and subjected to Masson trichrome staining for smooth muscle (SM)/collagen ratio, and immunostaining for a-smooth muscle actin (ASMA) for, SM content, proliferating cell nuclear antigen (PCNA) for cell replication, TGFb1 as profibrotic factor, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis, and xanthine oxidoreductase (XOR) for oxidative stress. Collagen was estimated by the hydroxyproline reaction. Results. The corporal SM/collagen ratio and SM content were reduced, and collagen content increased in iNOS KO mice as compared with WT mice, but apoptosis was decreased and cell replication increased, whereas TGFb1 and XOR did not vary. Severe hyperglycemia caused in the WT a reduction of the corporal SM/collagen ratio and SM content and an increase in apoptosis without changes in PCNA, TGFb1, or XOR. In the iNOS KO mouse the hyperglycemia-induced alterations were exacerbated, with additional increases in oxidative stress and TGFb1. Insulin normalized glycemia and partially protected the SM in both the WT and the iNOS KO mice. Conclusions. The antifibrotic, antioxidative, and SM-protective roles of iNOS in the penile corpora cavernosa were confirmed in the iNOS KO/STZ mouse model. These findings support the importance of endogenously-elicited iNOS induction in protecting the penile corpora cavernosa from the pro-fibrotic effects of hyperglycemia. Ferrini MG, Rivera S, Moon J, Vernet D, Rajfer J, and Gonzalez-Cadavid NF. The genetic inactivation of inducible nitric oxide synthase (iNOS) intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes. J Sex Med 2010;7:3033-3044.
Urology, 1997
We hypothesized that advanced glycation end product (AGE) formation contributes to erectile dysfunction (ED) by quenching nitric oxide. Our first goal was to identify the specific AGE pentosidine in the diabetic human penis. Because AGE-mediated effects may involve inducible nitric oxide synthase (iNOS), we performed immunohistochemical and Western blot analysis of diabetic and nondiabetic human penile tissue for iNOS. Finally, because AGEs may act intracellularly to affect proteins, we set out to identify endothelial NOS (eNOS) in the human penis as an initial step in examining a possible intracellular interaction between eNOS and AGEs. We performed high-performance liquid chromatographic analysis of diabetic human penile corpus cavernosum and serum for pentosidine and performed immunohistochemical, electron microscopic (EM), and Western blot analysis of the diabetic and nondiabetic penile corpus cavernosum and tunica for pyrraline, iNOS, and eNOS (and neural NOS [nNOS] for compara...
Journal of Diabetes, 2014
Background: Erectile dysfunction (ED) is a prevalent complication of diabetes , and oxidative stress is an important feature of diabetic ED. Oxidative stress-induced damage plays a pivotal role in the development of tissue alterations. However, the deleterious effects of oxidative stress in the corpus caver-nosum with the progression of diabetes remain unclear. The aim of this study was to evaluate systemic and penile oxidative stress status in the early and late stages of diabetes. Methods: Male Wistar streptozotocin-diabetic rats (and age-matched controls) were examined 2 (early) and 8 weeks (late) after the induction of diabetes. Systemic oxidative stress was evaluated by urinary H2O2 and the ratio of circulating reduced/oxidized glutathione (GSH/GSSG). Penile oxidative status was assessed by H2O2 production and 3-nitrotyrosine (3-NT) formation. Cavernosal endothelial nitric oxide synthase (eNOS) was analyzed by quantitative immunohistochemistry. Dual immunofluorescence was also performed for 3-NT and α-smooth muscle actin (α-SMA) and eNOS-α-SMA. Results: There was a significant increase in urinary H2O2 levels in both diabetic groups. The plasma GSH/GSSG ratio was significantly augmented in late diabetes. In cavernosal tissue, H2O2 production was significantly increased in late diabetes. Reactivity for 3-NT was located predominantly in cavernosal smooth muscle (SM) and was significantly reduced in late diabetes. Quantitative immunohistochemistry revealed a significant decrease in eNOS levels in cavernosal SM and endothelium in late diabetes. Conclusions: The findings indicate that the noxious effects of oxidative stress are more prominent in late diabetes. Increased penile protein oxidative modifications and decreased eNOS expression may be responsible for structural and/or functional deregulation, contributing to the progression of diabetes-associated ED.
Diabetes mellitus increases nitric oxide synthase in penises but not in major pelvic ganglia of rats
British Journal of Urology, 1995
Objective To determine the effect of diabetes mellitus (DM) on erectile function and evaluate the levels of nitric oxide synthetase (NOS) activity in streptozotocininduced diabetic rats. Materials and methods Rats were studied at 9 weeks and 1 4 weeks after the induction of DM by streptozotocin and compared with untreated control rats. Erectile potency was assessed physiologically by testing and recording mating behaviour. NOS activity was assayed in penile tissues and major pelvic ganglia (MPG) by conversion of [3H] L-arginine to [3H] citrulline. Histological, ultrastructural and immunohistochemical studies of penile tissues were performed in similar groups of rats. Results Diabetes mellitus adversely and significantly degraded all parameters of mating behaviour, thus indicating defective erectile potency. However, NOS activities in penile tissues from both groups of diabetic rats were significantly higher than those in controls (P<0.01). In MPG, NOS activities were not significantly different between diabetic and control rats (P> 0.05). Histological, ultrastructural and immunohistochemical studies of penile tissues revealed no significant differences between control and diabetic rats, indicating an intact effector organ (smooth muscles) in rats with up, to 14 weeks of DM. Conclusion The impotence frequently observed in diabetic subjects would suggest that despite the increase in NOS activity in the penis, the pharmacological action of nitric oxide is impaired.
International Journal of Andrology, 2003
The aim of this study is to investigate the role of nitric oxide (NO) stabile end products, membrane lipid peroxidation and antioxidant defensive mechanism in diabetic erectile dysfunction (ED) and compare these parameters with non-diabetic ED groups. We examined the penile cavernosal tissues, obtained from 22 patients who had undergone surgery of penile prostheses implantation, for the nitrite, nitrate, malondialdehyde (MDA) and glutathione (GSH) levels. Eight patients were suffering from diabetic erectile dysfunction (ED) and 14 patients had non-diabetic ED. Nitrite and nitrate levels were lower; MDA and GSH levels were higher in the diabetic group. There were statistically significant differences between diabetic and non-diabetic groups amongst the nitrite (p < 0.001), nitrate (p < 0.01), MDA (p < 0.001) and GSH (p < 0.01) levels. Our data provide evidence that NO deficiency, possibly due to the membrane lipid peroxidation and defective antioxidant defensive mechanism, may contribute to the development of diabetic ED and thus is involved in the pathogenesis of ED in diabetic patients.
Journal of the American Society of Nephrology, 2000
Long-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term (Ͻ18 mo, n ϭ 6) or long-term (Ͼ18 mo, n ϭ 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca 2ϩ-dependent
The Journal of Urology, 1998
Purpose: Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) is recognized as the central mediator of penile erection. This process appears to be mediated mainly by neuronal NOS (nNOS), which is localized to the nonadrenergic, noncholinergic innervation of the penis. However, the role of non-neuronal penile constituents (specifically the cavernosal smooth muscle), as well as other NOS isoforms in NO production in the human penis is not well understood. The present study evaluates the expression of non-neuronal (inducible and endothelial) isoforms of NOS in human penile cavernosal smooth muscle cells in culture.