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Molekularbiologische Ursachen der chronischen tubulointerstitiellen Nephritis bei Methylmalonazidurie-Patienten

Ruppert, Thorsten

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Abstract

The aim of this study was to investigate the renal pathogenesis of chronic tubulointerstitial nephritis in patients of methylmalonic aciduria, which causes chronic kidney failure. As a research model we chose proximal tubule epithelial cells of patients of methylmalonic aciduria. Since in some studies a multiple disturbance of mitochondrial energy metabolism has been shown to be the cause of organ failure in patients of methylmalonic aciduria, we focused first on a description of the energy metabolism of the proximal tubule epithelial cells. The decreased activity of phosphofructokinase 1 results in less flux and thus causes a deterioration of glycolysis. In context of the unsuccessful isolation of mitochondria, the decreased activity of mitochondrial aconitase, 2-oxoglutarate-dehydrogenesis complex and cytochrome c oxidase suggest a mitochondrial defect in proximal tubule epithelial cells of patients of methylmalonic aciduria that manifested structurally and functionally. The mitochondrial defect led further to increased ROS production, which could be increased even more by metabolic stress due to the application of glucose, pyruvate, methylmalonic acid, propionic acid and isoleucine. A higher amount of reduced glutathione and a lower amount of free glutathione due to higher concentration of ROS strengthened the hypothesis of increased oxidative stress in proximal tubule epithelial cells of patients of methylmalonic aciduria. Higher concentrations of ROS resulted in concert with increased expression of pIRE1 and degenerated endoplasmic reticulum with enlarged lumen, which were recognizable on electron micrographs, in stress of endoplasmic reticulum in proximal tubule epithelial cells of patients of methylmalonic aciduria. Reduced activity of mTORC1 (mammalian target of rapamycin complex 1) under metabolic stress and disturbances in the energy metabolism in proximal tubule epithelial cells of patients of methylmalonic aciduria indicated a positive regulation of autophagosome formation. In concert, structures surrounded by a double membrane were recognizable on electron micrographs, and the increased expression of P62 and LC3-II under metabolic stress led to the adoption of increased macro-autophagy. This could be confirmed by a higher amount of autolysosomes. It is known that inflammation of a tissue is always accompanied by the infiltration by cells of the immune system. With respect to cytokines required for recruitment of the immune system the expression of interleukin-8 was higher and its apical and basolateral secretion was stronger in proximal tubule epithelial cells of patients of methylmalonic aciduria. The strong correlation between autophagy and the secretion of interleukin-8 in proximal tubule epithelial cells of patients of methylmalonic aciduria pointed out that autophagy is a direct cause of the increased transcription of interleukin-8 or promotes indirectly causes of the transcription of interleukin-8. This can lead to an infiltration of the interstitium of the proximal tubule by neutrophils, macrophages and T cells. The inflammatory response is triggered further and leads over a long period to failure of kidney function.

Item Type: Dissertation
Supervisor: Fricker, Prof. Dr. rer. nat. Gert
Date of thesis defense: 18 March 2015
Date Deposited: 26 Mar 2015 13:05
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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