Expression of Inducible and Endothelial Nitric Oxide Synthases, Formation of Peroxynitrite and Reactive Oxygen Species in Human Chronic Renal Transplant Failure

Abstract

Nitric oxide (NO¡) is produced by NO synthases (NOS)and can interact with reactive oxygen species (ROS) to form peroxynitrite, which induces protein damage by formation of nitrotyrosine. NO¡ has a promotional effect on acute rejection. To investigate the role of NO¡ during chronic renal transplant failure (CRTF), we studied the expression of eNOS and iNOS in conjunction with H 2 O 2 production and the formation of nitrotyrosines. Nephrectomy material from 10 patients and 10 control kidneys was used in this study. Expression of iNOS, eNOS, nitrotyrosine and the presence of ROS-producing cells and macrophages were determined using immunohistochemistry. INOS expression in nonsclerosed glomeruli and interstitium was significantly increased in patients with CRTF (p ∞0.05). Glomerular eNOS expression was decreased in patients with CRTF compared with glomeruli of control kidneys (p ∞0.01). Nitrotyrosine and ROS positive cells were significantly increased in CRTF in the interstitium (p ∞0.05), but not in glomeruli. In summary, we found a marked interstitial increase in iNOS protein expression together with a decrease in glomerular eNOS expression in CRTF patients, associated with a significant increment in ROS and nitrotyrosine-positive cells in the interstitium. Our results suggest that loss of NO¡ production by glomerular eNOS in conjunction with an increased NO¡ production by interstitial iNOS, together with the formation of ROS and nitrotyrosine, is involved in the pathogenesis of CRTF.

Resident Macrophages are Involved in Intestinal Transplantation-Associated Inflammation and Motoric Dysfunction of the Graft Muscularis

“…NO, synthesized by the iNOS is produced during ischemiareperfusion injury, has a promotional effect on acute and chronic rejection and is one of the most important suppressors of postoperative intestinal smooth muscle contractility (12,31,32). Finally, the prototypical proinflammatory cytokine IL-6 is rapidly activated after intestinal manipulation, participates in leukocyte recruitment, shows functional activity within the muscularis and has been associated with intestinal allograft rejection (33)(34)(35).…”

Plasma bilirubin and late graft failure in renal transplant recipients

“…It has been shown that oxidative stress is important in the pathophysiology of chronic transplant dysfunction [6][7][8][9]. Chronic transplant dysfunction is the leading cause of a slow, but progressive decline in renal allograft function [3].…”

“…Frequently, the slow decline in graft function is not the consequence of immunological rejection, but an entity that is called chronic transplant dysfunction [3]. The exact pathophysiology is not known, but oxidative stress has been implicated [6][7][8][9]. Endogenous bilirubin is an established cytoprotectant and antioxidant [10][11][12].…”

“…It is, however, not known whether endogenous levels of bilirubin influence long-term renal outcome in RTR. Because oxidative stress has been implicated a detrimental role in the process of chronic transplant dysfunction [6][7][8][9], we hypothesized that high circulating bilirubin concentrations protect against late graft failure in RTR. We prospectively investigated this hypothesis with a large single-center cohort of RTR.…”

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“…Studies have shown that interstitial inducible nitric oxide synthase protein expression, nitrotyrosine, and ex vivo ROS production are increased in CAI. 44,45 The balance between the ROS production and antioxidant defenses defines the degree of OS in any given tissue. 45 Injury to the tubular epithelium causes endoplasmic reticulum (ER) stress and unfolded protein response, thereby releasing ROS leading to ischemiareperfusion injury.…”