Untersuchungen des Einflusses von Phosphorylierungen des Endozytose-Rezeptors Megalin sowie von Diabetes und Hypoxie auf die Funktion des proximalen Tubulus

The proximale tubule (PT) of the kidney reabsorbs most of water, salts, nutrients and proteins from the primary filtrate. Protein uptake occurs mainly via the receptor megalin and disturbances lead e. g. to proteinuria, a clinical symptom of many kidney diseases. Megalin is characterized by phosphorylations. The position serine 4577 is phosphorylated by the kinase complex mTORC1 and this lead to reduced endocytosis of albumin. This effect was not due to changes in intracellular distribution of megalin. The phosphorylation of serine 4577 had also no effect on serine 4616, a known site to influence megalins recycling. Another aspect of this thesis was to elucidate the role of hypoxia in the PT in diabetic nephropathy (DN). DN is a result of diabetic complications. With the onset of diabetes, glomerular hyperfiltration and microalbuminuria occur, which faces the PT to enhanced reabsorption and hypoxia. The role of hypoxia in the development and progression of DN is currently unknown. By using a new conditional knockout mice model in combination with type 1 diabetes mellitus the contribution of hypoxia in PT could be analyzed. PT hypoxia and DN share common alterations in glomerular and tubular morphology, tubular transport and metabolism. At the same time, hypoxia in PT prior diabetes induction prevented glomerular hyperfiltration compared to diabetic control mice. This was associated by a reduction of NOS1 and sodium-glucose transporters. RNA-sequencing analysis revealed genes, which may be responsible for improvement of DN. Among the most significantly altered genes Slc12a1 (sodium transporter NKCC2), Ldc1 (leucine decarboxylase 1) and the transcription factor Zbtb16 were identified. The catalyzed product of LDC1, isopentylamine, increased cellular oxygen consumption rate and ZBTB16 reduced autophagy. These data demonstrate that PT hypoxia is a hallmark of DN and that targeting hypoxia prior onset of type 1 diabetes may ameliorate development and progression of DN.


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