Protektive Effekte körperlicher Aktivität auf die Entwicklung der Nierenfibrose bei chronischer Niereninsuffizienz
Protective effects of physical activity on fibrogenesis in chronic kidney disease
by Anne-Christine Zygmunt
Date of Examination:2024-11-12
Date of issue:2024-12-20
Advisor:Prof. Dr. Michael Zeisberg
Referee:Prof. Dr. Dr. Albrecht Neeße
Referee:Prof. Dr. Ralf Dressel
Persistent Address:
http://dx.doi.org/10.53846/goediss-10897
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Abstract
English
The rising prevalence of chronic kidney disease (CKD) with its limited therapeutic options still poses a relevant clinical dilemma. Especially therapies that ameliorate the histopathological correlate, i.e. renal fibrosis, are rare. Thus, the need for causal therapeutic targets and inhibitors of disease progression that are widely applicable and low in side effects remains. In general, we understand that exercise is benefitial to the body and it can protect from the occurance and progress of many diseases, such as chronic kidney pathologies. It is also capable of improving illnesses such as diabetes or cardiovascular diseases which are tightly linked to CKD and its' progression. This has been shown in an abundance of studies. However the majority of the underlying mechanisms remain unclear. Also, the axis of communication between skeletal muscle as the contracting organ in exercise and the (diseased) kidney is still subject of debate. In this study we demonstrate protective effects of physical activity in the UUO-model in mice. C57BL/6-mice were either exposed to endurance exercise via hamster wheel or left sedentary for four weeks without access to increased physical activity. After this, unilateral ureteral obstruction (UUO) was performed for seven days, after which the mice were euthanised and organs and blood harvested. The damaged UUO-kidneys showed significantly less fibrosis (i.e. collagen-1-deposition) in the exercise group than the sedentary group. MMP-2 and -9, as well as pro-MMP-9, were simultaneously upregulated in the UUO-kidney of exercise trained mice, possibly degrading excessive extracellular matrix (ECM) and therefore ameliorating fibrosis. In search of the axis of communication between skeletal muscle and the damaged kidney, we isolated exosomes containing microRNA (miR) from plasma of sedentary and active mice. Results showed an exercise-induced abundance of several microRNA, especially miR-10a. Hereafter UUO-kidneys and skeletal muscle were analysed for the same miRs via PCR-Array. UUO-kidneys of the exercise group, congruently to plasma, showed significantly elevated levels of miR-10a. Meanwhile the skeletal muscle showed significantly down regulated miR-10a, suggesting that physical activity results in the secretion of miR from organs such as the skeletal muscle which then arrives at the site of the damaged kidney in need of repair via exsosomes. We postulate that miR, contained in exosomes secreted from skeletal muscle in response to exercise and transported to the kidney via blood stream, may be involved in the observed protection from fibrosis in damaged kidneys. Effects could be mediated by miR, modulating profibrotic pathways, for example via miR-interference of gene expression, resulting in an observed induction of MMPs and therefore ECM-reduction. While further studies on the axis of communication and postulated underlying mechanisms are needed to further consolidate our hypothesis, the idea of a protective treatment, capable of attenuating renal fibrosis as shown in our study and available to anyone, is very attractive.
Keywords: renal fibrosis; kidney fibrosis; exercise; fibrogenesis; chronic kidney disease; protection; microRNA; exosomes
Schlagwörter: Nierenfibrose; Chronische Nierenerkrankung; Ausdauertraining; Fibrogenese; microRNA; Exosomen; Protektive Effekte
