Serelaxin-vermittelte Inhibition von Fibroblastenaktivierung bei renaler Fibrogenese

Attenuating fibroblast activation and kidney fibrosis in CKD patients with Serelaxin

by Friederike Hesse
Doctoral thesis
Date of Examination:2019-04-03
Date of issue:2019-03-21
Advisor:Prof. Dr. Michael Zeisberg
Referee:PD Dr. Frauke Czepluch
Referee:Prof. Dr. Margarete Schön
Persistent Address: http://dx.doi.org/10.53846/goediss-7336

 

 

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Abstract

English

Progression of chronic kidney disease (CKD) towards end stage renal failure remains an unsolved problem in nephrology. Regardless of the primary underlying disease, chronically injured kidneys are histomorphologically characterized by tubulointerstitial fibrosis. Current management of CKD mainly aims at treating underlying conditions and cardiovascular risk factors. As CKD is commonly associated with hypertension, most prevalent pharmacological interventions include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), beta blockers, diuretics, statins and calcium channel blockers. Preclinical studies showed favourable antifibrotic effects from the recombinant human relaxin-2 hormone, Serelaxin. Relaxin is a hormone primarily produced by pregnant females. It not only mediates the hemodynamic changes that occur during pregnancy, (i.e. increased cardiac output and increased renal blood flow) but also facilitate relaxation of pelvic ligaments and soften the pubic symphysis. Here the study suggests that CKD is associated with loss of relaxin-1 and relaxin-2, whereas relaxin receptors Rxfp1 and Rxfp2 are upregulated in interstitial myofibroblasts during fibrosis. Furthermore, it provides proof that Serelaxin attenuates fibroblast activation in vitro and renal fibrosis in two different rodent models (UUO + FA) in vivo. Loss of relaxin in kidney fibrosis is caused by aberrant promotor CpG island methylation and subsequent transcriptional gene silencing. Additionally, this study identified that circulating methylated RLN promotor DNA fragments in peripheral blood correspond with levels of intrarenal levels of RLN promotor methylation and degree of fibrosis in kidney biopsies. Thus, this study adds further evidence for a contribution of aberrant promoter CpG island methylation to the progression of renal fibrogenesis and its potential as a biomarker and therapeutic target.
Keywords: DNA methylation; Serelaxin; kidney fibrosis
 
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