The Potential Role of Advanced Glycation End Product and iNOS in Chronic Renal Failure-Related Testicular Dysfunction

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 of AGE and iNOS in experimental CRF-associated testicular dysfunction. In addition, we found that PD fluids containing glucose contribute to this effect. These results may lead to a better understanding of the pathophysiological pathway in CRF-related testicular dysfunction.

Expression of vascular endothelial growth factor and transforming growth factor alpha in rat testis during chronic renal failure

“…However, Adachi et al applied a stepwise-nephrectomy procedure and demonstrated that testicular histology has not been affected by CRF in rats [43]. This observation is compatible with our previous results that the testicular histology between the CRF and control groups was not statistically different based on the Johnsen's scores [30].…”

“…During the same session, after mobilizing the adrenal gland, the right kidney was removed after ligation of the renal artery, vein, and ureter. This procedure resulted in a resection of more than 85% of the renal tissue as previously described [30].…”

“…Afterwards, ceftazidime (125 mg/L) and gentamicin (8 mg/L) were given intraperitoneally. This procedure was continued until the beginning of chronic peritoneal dialysis (PD) [30]. Each morning, the Luer-Lock adaptor was removed and a sterile catheter was passed through the permanent indwelling catheter and rinsed with 20 mL prewarmed saline.…”

Paracrine Modulation of Androgen Synthesis in Rat Leydig Cells by Nitric Oxide

“…While L‐NAME potently blocked l ‐[ 14 C]citrulline accumulation in various male rat reproductive tissues, this activity in the testis could be reduced by only 50% (Burnett et al, 1995). Using immunohistochemical techniques, eNOS has been detected in rat Sertoli, Leydig, and germ cells (Zini et al, 1996), nNOS was identified in Leydig cells by immunocytochemistry (Lissbrant et al, 1997), and constitutively expressed iNOS was proposed as a modulator of T production in these cells (O'Bryan et al, 2000a; Koksal et al, 2003). Nevertheless, these studies did not demonstrate enzyme activity in Leydig cells, and, in fact, it has been argued that the absence of NADPH‐diaphorase activity in Leydig cells indicates the existence of an inactive form of nNOS (Lissbrant et al, 1997).…”

Male Sexual Dysfunction and Chronic Kidney Disease

“…The endocrine derangements described earlier go some way to accounting for abnormal sperm production. The presence of oxidative stress has also been identified as a potential contributor to testicular dysfunction (77, 78). Oxidative stress is induced by various inflammatory pathways in CKD and exacerbated by the use of glucose-based peritoneal dialysis solutions or the extracorporeal circuit in hemodialysis.…”