The potential role of perivascular lymphatic vessels in preservation of kidney allograft function

Tsuchimoto, Akihiro; Nakano, Toshiaki; Hasegawa, Shoko; Masutani, Kosuke; Matsukuma, Yuta; Eriguchi, Masahiro; Nagata, Michio; Nishiki, Takehiro; Kitada, Hidehisa; Tanaka, Masao; Kitazono, Takanari; Tsuruya, Kazuhiko

doi:10.1007/s10157-016-1338-9

Cited by 13 publications

(17 citation statements)

References 33 publications

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“…18 Another study demonstrated kidney transplants with higher perivascular lymphatic density had a reduced proportion with progression of interstitial fibrosis/tubular atrophy grade from 3-12 months posttransplant and was associated with a reduced rate of estimated glomerular filtration rate decline after 12 months. 19 In line with this, VEGF-C overexpression in mouse kidney allografts significantly attenuated acute rejection 20 ( Figure 2B). Overall, perivascular lymphatic density or lymphatic density in proximity to TLOs may be the best indicators of early outcomes in kidney transplants, in part, related to their ability to provide a route for immune cell emigration.…”

Section: Kidney Transplantationsupporting

confidence: 69%

“…Sequential biopsies in human kidney transplants revealed that grafts with higher lymphatic densities within nodular areas of cellular infiltrates (resembling TLOs) had improved kidney functional outcomes compared to those with lower LV density 1 year posttransplant . Another study demonstrated kidney transplants with higher perivascular lymphatic density had a reduced proportion with progression of interstitial fibrosis/tubular atrophy grade from 3‐12 months posttransplant and was associated with a reduced rate of estimated glomerular filtration rate decline after 12 months . In line with this, VEGF‐C overexpression in mouse kidney allografts significantly attenuated acute rejection (Figure B).…”

Section: Role Of Lymphangiogenesis In Solid Organ Transplantationmentioning

confidence: 64%

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Lymphatic vessels in solid organ transplantation and immunobiology

Wong

2020

American Journal of Transplantation

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endothelial hyaluronan receptor 1; MALT, mucosa-associated lymphoid tissue; mTOR, mechanistic target of rapamycin (also known as mammalian target of rapamycin); mTORC1, mechanistic target of rapamycin complex 1; NFAT, nuclear factor of activated T cells; NFκB, nuclear factor kappa B; NRP2, neuropilin 2; PDPN, podoplanin; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PROX1, prospero homeobox transcription factor 1; SLO, secondary lymphoid organ; TGFβ1, transforming growth factor beta 1; TLO, tertiary lymphoid organ; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VEGF-A, vascular endothelial growth factor A; VEGF-C, vascular endothelial growth factor C; VEGF-D, vascular endothelial growth factor D; VEGFR3, vascular endothelial growth factor receptor 3 (known as Flt4 in the mouse).

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Section: Kidney Transplantationsupporting

confidence: 69%

Section: Role Of Lymphangiogenesis In Solid Organ Transplantationmentioning

confidence: 64%

Lymphatic vessels in solid organ transplantation and immunobiology

Wong

2020

American Journal of Transplantation

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“…We have previously reported that a high perivascular lymphatic density in kidney transplant patients is associated with the kidney allograft prognosis. 8 The best known factors to promote lymphangiogenesis are vascular endothelial growth factor (VEGF)-C and VEGF-D. VEGF-C binds to VEGF receptor-2 (VEGFR-2) and VEGFR-3, which plays a crucial role in proliferation, migration, and survival of lymphatic endothelial cells (LECs) via VEGFR-3, 9 and has lesser effects on blood vessels via VEGFR-2. [10][11][12] VEGF-C deficiency results in embryonic death of mice.…”

mentioning

confidence: 99%

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction

Hasegawa

Nakano

Torisu

et al. 2017

Laboratory Investigation

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Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-β1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

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“…Although our study demonstrated the lymphangiogenesis could deteriorate the function of renal allografts, some previous studies reported that lymphangiogenesis could prolong the life span of recipients with better renal functions both in mouse and human kidney transplant, which is totally contrary to our findings ( 35 , 55 ). In parallel, a clinical study revealed human biopsy studies demonstrated kidney transplants with higher perivascular lymphatic density had a reduced proportion with progression of interstitial fibrosis/tubular atrophy grade ( 56 ). These studies held the perspective that LVs give play to provide excurrent pathways for cellular infiltration, and thus prevent continuous alloimmune responses in renal allografts.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic Reconstruction in Kidney Allograft Aggravates Chronic Rejection by Promoting Alloantigen Presentation

et al. 2021

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Chronic rejection of the renal allograft remains a major cause of graft loss. Here, we demonstrated that the remodeling of lymphatic vessels (LVs) after their broken during transplantation contributes to the antigen presenting and lymph nodes activating. Our studies observed a rebuilt of interrupted lymph draining one week after mouse kidney transplantation, involving preexisting lymphatic endothelial cells (LECs) from both the donor and recipient. These expanding LVs also release C-C chemokine ligand 21 (CCL21) and recruit CCR7+ cells, mainly dendritic cells (DCs), toward lymph nodes and spleen, evoking the adaptive response. This rejection could be relieved by LYVE-1 specific LVs knockout or CCR7 migration inhibition in mouse model. Moreover, in retrospective analysis, posttransplant patients exhibiting higher area density of LVs presented with lower eGFR, severe serum creatinine and proteinuria, and greater interstitial fibrosis. These results reveal a rebuilt pathway for alloantigen trafficking and lymphocytes activation, providing strategies to alleviate chronic transplantation rejection.

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The potential role of perivascular lymphatic vessels in preservation of kidney allograft function

Abstract: High perivascular lymphatic density is associated with favourable kidney allograft function. The perivascular lymphatic network may be involved in inhibition of allograft fibrosis and stabilization of graft function.

Cited by 13 publications

References 33 publications

Lymphatic vessels in solid organ transplantation and immunobiology

Lymphatic vessels in solid organ transplantation and immunobiology

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction

Lymphatic Reconstruction in Kidney Allograft Aggravates Chronic Rejection by Promoting Alloantigen Presentation

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