Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine

Abstract

The major side effect of cyclosporin A is severe nephrotoxicity. It is likely that cyclosporin A causes vasoconstriction leading to hypoxia-reperfusion injury; therefore, these experiments were designed to attempt to obtain physical evidence for hypoxia and free radical production in kidney following cyclosporin A. Rats were treated daily with cyclosporin A (25 mg/kg ig) for 5 days, and pimonidazole, a hypoxia marker, was injected 2 h after the last dose of cyclosporin A. A dose of α-(4-pyridyl-1-oxide)- N- tert-butylnitrone (4-POBN) was injected 3 h after cyclosporin A to trap free radicals. Cyclosporin A doubled serum creatinine and decreased glomerular filtration rates by 65% as expected. Pimonidazole adduct binding in the kidney was increased nearly threefold by cyclosporin A, providing physical evidence for tissue hypoxia. Moreover, cyclosporin A increased 4-POBN/radical adducts nearly sixfold in the urine but did not alter levels in the serum. Glycine, which causes vasodilatation and prevents cyclosporin A toxicity, minimized hypoxia and blocked free radical production; however, it did not alter cyclosporin A blood levels. These results demonstrate for the first time that cyclosporin A causes hypoxia and increases production of a new free radical species exclusively in the kidney. Therefore, it is concluded that cyclosporin A causes renal injury by mechanisms involving hypoxia-reoxygenation, effects which can be prevented effectively by dietary glycine.

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…It has previously been suggested that aggravated low oxygen tension in the renal medulla may cause progression of nephropathy [5,6]. In view of our previous [8] and present results with markedly decreased renal tissue oxygen tension during chronic hyperglycaemia, we conducted separate experiments applying microdialysis to assess the regional interstitial metabolic environment in vivo.…”

“…The majority of studies on diabetic nephropathy have been conducted in vitro and/or have focused on glomerular changes. In the kidney, the medullary region is particularly vulnerable to decreased oxygen concentration because of its low blood perfusion and high basal oxygen consumption [5,6]. Even during normal situations, the renal medulla works at the threshold of hypoxia [5,6] and has an oxygen extraction from the blood of about 90% [7].…”

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

“…Steep oxygen gradients would foreshorten the distance over which divergent K m s are traversed, possibly reducing the distance to the two or three cell diameters observed in moderately differentiated tumours ( Figure 4C and D) and in normal tissues such as the liver and kidney (Arteel et al, 1995;Zhong et al, 1998). Conversely, shallow gradients would increase the distance over which divergent K m s are traversed allowing for involucrin induction in advance of pimonidazole binding as appears to be the case in Figure 4A and B.…”

Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension

“…Surgically induced renal ischaemia has also been shown to accelerate the progression of nephropathy in STZ-diabetic rats [24]. In the kidney, the renal medullary region is particularly vulnerable to decreased tissue oxygen tension because of its low blood perfusion and high basal oxygen consumption [25,26]. Already during normal circumstances, the renal medulla works at the threshold of hypoxia [25,26] and has an oxygen extraction rate of about 90% [27].…”