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2015 ; 8
(8
): 919-30
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Targeting tubulointerstitial remodeling in proteinuric nephropathy in rats
#MMPMID26035383
Yazdani S
; Hijmans RS
; Poosti F
; Dam W
; Navis G
; van Goor H
; van den Born J
Dis Model Mech
2015[Aug]; 8
(8
): 919-30
PMID26035383
show ga
Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric
interventions are not always successful, and residual proteinuria often leads to
renal failure. This indicates the need for additional treatment modalities by
targeting the harmful downstream consequences of proteinuria. We previously
showed that proteinuria triggers renal lymphangiogenesis before the onset of
interstitial inflammation and fibrosis. However, the interrelationship of these
interstitial events in proteinuria is not yet clear. To this end, we specifically
blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte/macrophage influx
(clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist
FTY720) separately in a rat model to investigate the role and the possible
interaction of each of these phenomena in tubulointerstitial remodeling in
proteinuric nephropathy. Proteinuria was induced in 3-month old male Wistar rats
by adriamycin injection. After 6?weeks, when proteinuria has developed, rats were
treated for another 6?weeks by anti-VEGFR3 antibody, clodronate liposomes or
FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of
macrophages, T cells and myofibroblasts, and collagen III deposition and
interstitial fibrosis significantly increased at week 12 vs week 6. Anti-VEGFR3
antibody prevented lymphangiogenesis in proteinuric rats, however, without
significant effects on inflammatory and fibrotic markers or proteinuria.
Clodronate liposomes inhibited macrophage influx and partly reduced myofibroblast
expression; however, neither significantly prevented the development of
lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented
myofibroblast accumulation, T-cell influx and interstitial fibrosis, and
partially reduced macrophage number and proteinuria; however, it did not
significantly influence lymphangiogenesis and collagen III deposition. This study
showed that proteinuria-induced interstitial fibrosis cannot be halted by
blocking lymphangiogenesis or the influx of macrophages. On the other hand,
FTY720 treatment did prevent T-cell influx, myofibroblast accumulation and
interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We
conclude that tubulointerstitial fibrosis and inflammation are separate from
lymphangiogenesis, at least under proteinuric conditions.
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