Transforming Growth Factor-Beta in Kidney Transplantation: A Double-Edged Sword

Du, Caigan

doi:10.5772/20450

Cited by 7 publications

(5 citation statements)

References 74 publications

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“…In preclinical transplantation studies, TGF-β1 was shown to protect against brain death-induced organ damage and ischaemia–reperfusion injury, and to prolong graft survival [ 43–46 ]. The mechanisms behind these protective effects include (i) protecting kidney cells against apoptosis, (ii) stimulating tissue regeneration and (iii) diminishing alloimmunity to kidney transplants by inducing tolerance through regulatory T cells [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

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A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation

Poppelaars

Costa

Faria

et al. 2021

Clinical Kidney Journal

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Introduction Improvement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exist about the effect of transforming growth factor-beta 1 (TGF-β1) on kidney transplant survival since TGF-β1 has pro-fibrotic and protective effects. We investigated the impact of a recently discovered functional TGBF1 polymorphism on kidney graft survival. Methods We performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival. Results Donor genotype frequencies of rs1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.014). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.12 for the T-allele; 95%-CI 1.18–3.79; P=0.012). The incidence of graft loss within 15 years of follow-up was 16.4% in the CC-genotype group and 31.6% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss. Conclusion Kidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-β1 is beneficial, rather than harmful, for kidney transplant survival.

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Section: Discussionmentioning

confidence: 99%

“…In kidney transplantation, TGF-β1 has been a topic of interest for many years and TGF-β1 has been suggested to impact allograft survival in different ways [ 12 ]. Initially, multiple reports showed upregulation of TGF-β1 expression and signalling in kidney transplants during rejection [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation

Poppelaars

Costa

Faria

et al. 2021

Clinical Kidney Journal

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“…As galunisertib is a potent inhibitor of the TGFβ1 signalling pathway (Isaka, 2018), one of the main concerns of systemic inhibition of TGFβ signalling is the interference with beneficial biological processes, leading to adverse effects (Huang et al, 2021). Furthermore, the effects of TGFβ1 up‐regulation during renal transplantation have shown contradictory results (Du, 2011). Although we could not measure systemic effects of galunisertib in our isolated perfusion model, we did analyse the effects of galunisertib on renal function, injury and viability, of which none were compromised.…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

van Leeuwen,

Ruigrok,

Kessler

et al. 2023

British J Pharmacology

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Background and purposeFibrosis in kidney allografts is a major post‐transplant complication that contributes to graft failure. Lately, multiple potent inhibitors of fibrosis‐related pathways have been developed such as galunisertib—an inhibitor of the transforming growth factor‐beta (TGF‐β) signaling pathway. This drug, however, poses risks for adverse effects when administered systemically. Therefore, we devised a new repurposing strategy in which galunisertib is administered ex vivo. We combined machine perfusion and tissue slices to explore the antifibrotic effects of galunisertib in renal grafts.Experimental approachPorcine kidneys were subjected to 30 min of warm ischemia, 24 h of oxygenated hypothermic machine perfusion, and 6 h of normothermic machine perfusion with various treatments (i.e., untreated control, TFG‐β, galunisertib, or TGF‐β+galunisertib; n=8 kidneys per group). To determine whether effects persisted upon ceasing treatment, kidney slices were prepared from respective kidneys and incubated for 48 h.Key resultsGalunisertib treatment improved general viability without negatively affecting renal function or elevating levels of injury markers or byproducts of oxidative stress during perfusion. Galunisertib also reduced inflammation and more importantly, reduced the onset of fibrosis after 48 h incubation.Conclusions and implicationsOur findings demonstrate the value of using machine perfusion for administering anti‐ fibrotic drugs, such as galunisertib, proving it to be an effective example of repurposing.

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“…TGF-␤ has been proposed as a therapeutic target for preventing renal allograft fibrosis (16,17,30). The present study for the first time demonstrates that neutralizing activities of both TGF-␤ isoforms (TGF-␤1 and TGF-␤2) using an anti-TGF-␤ antibody (11D1) successfully reduces the severity of CR of renal allografts in a rat model; compared with a control antibody (clone 13C4)-treated group, administration of anti-TGF-␤ monoclonal antibody (1D11) is associated with a significant reduction of proteinuria, serum creatinine, and BUN in kidney transplant recipients, or prevents creatinine clearance decline in kidney transplants.…”

Section: Discussionmentioning

confidence: 99%

“…How the inactivation of TGF-␤1 and TGF-␤2 reduces the severity of CR in kidney transplants is not completely understood as yet. It has been proposed that chronic injury in kidney transplants causes dysfunction of resident TECs, which triggers release of TGF-␤ and recruitment of inflammatory cells to injured kidneys (17). In addition to lymphocytes and monocytes/MØs, kidney cells also produce TGF-␤ in response to the stimulation of proinflammatory/cell injury factors, such as interleukin-1␤ and TNF-␣ (20,51).…”

Section: Discussionmentioning

confidence: 99%

Reduction of chronic rejection of renal allografts by anti-transforming growth factor-β antibody therapy in a rat model

Guan

Gao

et al. 2013

American Journal of Physiology-Renal Physiology

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There is no effective treatment for chronic rejection (CR) that largely limits long-term survival of kidney transplants. Transforming growth factor (TGF)-β is a fibrogenic factor for tissue fibrosis. This study was to test the efficacy of an anti-TGF-β antibody in preventing the CR of renal allografts in a preclinical model. Male Lewis rats (RT1¹) were orthotopically transplanted with donor kidneys from male Fischer 344 (RT11v1) rats and were treated with either anti-TGF-β or a control antibody. The CR of renal allografts was assessed by semiquantitative histological analyses, and intragraft cytokines and fibrosis-related genes ware examined by PCR arrays. Compared with the control antibody, anti-TGF-β antibody treatment significantly reduced recipients' proteinuria (P = 0.0002), and CR in renal transplants, which was indicated by the fewer injured renal tubules, glomeruli, and interlobular arterioles or arteries, and by less mononuclear cell infiltration and interstitial fibrosis in the anti-TGF-β antibody-treated group (P < 0.05), but not significantly attenuate the ratios of different infiltrating leukocytes. These pathological changes were associated with downregulation of TGF-β1, TGF-β2, and proinflammatory cytokines, or with upregulation of anti-fibrotic HGF, BMP5, and BMP7. The therapeutic effect of the anti-TGF-β antibody was further confirmed by its prevention of graft dysfunction, indicated by lower levels of serum creatinine and blood urea nitrogen or higher creatinine clearance in anti-TGF-β antibody-treated recipients compared with those in control recipients (P < 0.05). In conclusion, the anti-TGF-β antibody (1D11) treatment significantly reduces CR of renal allografts in rats, suggesting the therapeutic potential of this antibody therapy for treating CR of kidney transplants in patients.

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Transforming Growth Factor-Beta in Kidney Transplantation: A Double-Edged Sword

Cited by 7 publications

References 74 publications

A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation

A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation

Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

Reduction of chronic rejection of renal allografts by anti-transforming growth factor-β antibody therapy in a rat model

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