Targeting tubulointerstitial remodeling in experimental proteinuric nephropathy

Hijmans, R.S. (Ryanne) (2014) Targeting tubulointerstitial remodeling in experimental proteinuric nephropathy. thesis, Medicine.

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Abstract

Introduction Proteinuria is an important cause of progressive tubulointerstitial damage, worsening to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Clinically, current anti-proteinuric interventions are not always successful, and residual proteinuria leads to advanced renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. It is already been shown that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these three interstitial events in proteinuria is not clear yet. Aim of the study The aim of this study is to specifically block lymphangiogenesis, inflammation and fibrosis in a proteinuric model, to investigate the possible interaction of these tubulointerstitial phenomena. Method Proteinuria was induced in 60 male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria developed, the rats were randomly assigned to one of the treatment or control groups. The treatment was started for 6 consecutive weeks with anti-VEGFR3 antibody (IMC-3C5) for blocking lymphangiogenesis, clodronate liposomes for blocking monocyte/macrophage influx, or FTY720 for blocking of the T-cell influx and fibrosis. At week 12, after the collection of blood and urine, and blood pressure measurement, rats were sacrificed and organs were harvested for immunohistochemistry and qRT-PCR. Results In proteinuric rats, lymphangiogenesis (podoplanin+ vessels), inflammation (ED1+ macrophages and T cells), pro-fibrosis (α-SMA+ cells), and fibrosis (collagen III) significantly increased at week 12 vs. week 6. IMC-3C5 antibody completely blocked lymphangiogenesis in proteinuric rats, but had no effect on inflammation, (pro)fibrosis or proteinuria. Clodronate liposomes completely inhibited macrophage influx, partly reduced myofibroblast expression (α-SMA), however, neither prevented lymphangiogenesis, fibrosis and proteinuria. FTY720 completely prevented myofibroblast accumulation and T cell influx, partially declined macrophage number and proteinuria, however, it did not influence lymphangiogenesis and fibrosis. Conclusion Specific blocking of lymphangiogenesis, pro-fibrosis or inflammation does not seem to have an influence on each other. The results showed that these are rather independent tissue remodeling responses, at least under proteinuric conditions. It proposes that, for the treatment of the downstream consequences of proteinuria there is no specific promising target in one of the tubulointerstitial changes that we investigated in this study.

Item Type:	Thesis (Thesis)
Supervisor name:	Born, Dr. J. van den and Yazdani, drs. S.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:50
Last Modified:	25 Jun 2020 10:50
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1101

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