Haeringen, W.N. van (2013) De rol van 5’-AMP en H2S in bescherming van cellen tegen oxidatieve stress tijdens en na torpor. thesis, Medicine.
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Abstract
During cardiothoracic surgery, therapeutic hypothermia is frequently used to limit neuronal ischemia, as a reduction in metabolism is thought to lower the need for oxygen. Cooling and rewarming, however, causes inadequate renal perfusion, resulting in ischemia-reperfusion injury: a condition in which restoration of circulation results in the formation of reactive oxygen species. This causes an inflammatory response which may lead to massive apoptotic cell death and necrosis of tissue. Hibernation may prove a safer way of metabolic suppression. Despite repetitive bouts of cooling (torpor) and rewarming (arousal), hibernators show no gross signs of organ damage. Both 5’-adenosine monophosphate (5’-AMP) and hydrogen sulfide (H2S) are known to induce a torpor-like state in non-hibernating species and to increase resistance against hypothermia, ischemia and reperfusion. AMP-kinase (AMPK) is a sensor of cellular energy content and is activated by 5’-AMP. Cystathionine-β-synthase (CBS) is involved in the endogenous production of H2S and might be activated by 5’-AMP as well. This study investigated the role of 5’-AMP and H2S in protection against oxidative stress. In hamsters we studied whether pharmacological induction of torpor by 5’-AMP causes kidney damage and if simultaneous inhibition of CBS increases damage. Furthermore, the assumed protection of 5’-AMP and H2S against metabolic stress was studied in vitro in a human and a rat cell culture model for oxidative stress. Histological and immunohistochemical analysis of kidney slices showed that 5’-AMP-induced torpor causes some degree of tubular damage in hamster kidneys, that is increased after inhibition of CBS. Potential factors that may have caused 5’-AMP-induced renal damage, are induction of apoptosis by activation of adenosine receptors or paradoxically by activation of AMPK, depletion of ATP by adenylate kinase and the induced hypothermia itself. Hypothermia is assumed to be the most likely cause, as it is the only factor that has a distinct association with kidney injury. It is possible that AMPK and CBS were in fact activated by 5’-AMP, but that this was not sufficient to overcome the detrimental effects of hypothermia on the kidney completely. Blocking CBS increased cortical tubular damage in the kidney, which stresses the role of H2S and AMPK in protection against metabolic stress In vitro. 5’-AMP did not protect cells against oxidative stress, nor did it activate AMPK in our cell models. Presumably, activation of AMPK was prevented by a high glucose concentration in the culture medium. In vitro we found a possible protective effect of H2S on oxidative stress in human cells. Future experiments are needed to optimize the timing of H2S administration. Our results confirm the role of CBS in protection against oxidative stress. On the other hand, 5’-AMP failed to protect hamsters and cultured cells against oxidative stress. Presumably, the effect of 5’-AMP is very much dependent on the metabolic state of the animal / the cells. This is an important target for future research.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Henning, prof. dr. R.H. |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:59 |
| Last Modified: | 25 Jun 2020 10:59 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1964 |
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