Serine Protease Inhibitor-6 Inhibits Granzyme B–Mediated Injury of Renal Tubular Cells and Promotes Renal Allograft Survival

Lau, Arthur; Khan, Karim M.; Pavlosky, Alex; Yin, Ziqin; Huang, Xiaohang; Haig, Aaron; Liu, Weihua; Singh, Bhagirath; Zhang, Zhu‐Xu; Jevnikar, Anthony M.

doi:10.1097/tp.0000000000000237

Cited by 13 publications

(17 citation statements)

References 35 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17 Finally, the murine homolog of serine protease inhibitor-9 (serine protease inhibitor-6) was demonstrated to be renoprotective during allograft inflammation by inhibiting the activity of granzyme B. 18 Taken together, these data show excellent concordance between mRNA, protein expression, and activity data, and concordance between human and animal findings.…”

Section: Transplantation and Human -Omicsmentioning

confidence: 79%

“…41 Several serine proteases and their cognate inhibitors have been implicated in subclinical and clinical rejection, such as granzymes A/B and serine protease inhibitor-9. [16][17][18]43,44 More recently, it has been reported that granzyme B + regulatory B cells are increased in transplant patients, and it is suggested that these regulatory B cells may play a role in maintaining transplant tolerance and host defense. 45 SERP-1 is a serine protease inhibitor that inhibits tissuetype and urokinase-type plasminogen activators, thrombin, factor Xa, and plasmin and has been shown to inhibit early injury and chronic allograft rejection in a rat renal transplant model.…”

Section: Serine Hydrolase Enzyme Familymentioning

confidence: 99%

See 1 more Smart Citation

Activity-based Protein Profiling Approaches for Transplantation

et al. 2019

View full text Add to dashboard Cite

Enzyme activity may be more pathophysiologically relevant than enzyme quantity and is regulated by changes in conformational status that are undetectable by traditional proteomic approaches. Further, enzyme activity may provide insights into rapid physiological responses to inflammation/injury that are not dependent on de novo protein transcription. Activity-based protein profiling (ABPP) is a chemical proteomic approach designed to characterize and identify active enzymes within complex biological samples. Activity probes have been developed to interrogate multiple enzyme families with broad applicability, including but not limited to serine hydrolases, cysteine proteases, matrix metalloproteases, nitrilases, caspases, and histone deacetylases. The goal of this overview is to describe the overall rationale, approach, methods, challenges, and potential applications of ABPP to transplantation research. To do so, we present a case example of urine serine hydrolase ABPP in kidney transplant rejection to illustrate the utility and workflow of this analytical approach. Ultimately, developing novel transplant therapeutics is critically dependent on understanding the pathophysiological processes that result in loss of transplant function. ABPP offers a new dimension for characterizing dynamic changes in clinical samples. The capacity to identify and measure relevant enzyme activities provides fresh opportunities for understanding these processes and may help identify markers of disease activity for the development of novel diagnostics and real-time monitoring of patients. Finally, these insights into enzyme activity may also help to identify new transplant therapeutics, such as enzymespecific inhibitors.

show abstract

Section: Transplantation and Human -Omicsmentioning

confidence: 79%

Section: Serine Hydrolase Enzyme Familymentioning

confidence: 99%

Activity-based Protein Profiling Approaches for Transplantation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Acute kidney injury is a critical syndrome caused by ischaemic or renotoxicity insults and is characterized by acute tubular necrosis and renal dysfunction . Improving the renal tubular epithelial cell (TEC) regeneration and functional recovery has been considered as a key to attenuating the outcome of AKI . Previous studies have suggested that stem cells, such as bone marrow‐derived mesenchymal stem cells (BMSC), could be incorporated into post‐ischaemic renal tubules or enhanced tubular survival .…”

Section: Discussionmentioning

confidence: 99%

Nephropreventing effect of hypoxia‐inducible factor 1α in a rat model of ischaemic/reperfusion acute kidney injury

Wang

Liu

et al. 2018

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Acute kidney injury (AKI) occurs in 5% of hospitalized patients and in 50% of sepsis patients with acute renal dysfunction. However, there have been no safe and effective therapeutic strategies. The hypoxia condition is closely related to renal injury and function under AKI. As hypoxia-inducible factor 1α (HIF-1α) is critical for the cellular response to hypoxia, we investigated the protective effect of HIF-1α in a rat AKI model. We found that HIF-1α injection improved the survival of rat with AKI, and the level of creatinine and blood urea nitrogen (BUN) was also increased. Our data showed that HIF-1α treatment significantly alleviated ischaemic/reperfusion injury to kidney tubules and nephrocytes. We also found the downstream factors, such as EPOR, VEGF, and PHD3, were also upregulated by HIF-1α. Finally, it was observed that HIF-1α treatment also increased the percentage of adult resident progenitor cells (ARPC) in vitro and in vivo. In conclusion, HIF-1α plays a protective role in the ischaemic AKI model through stimulating the proliferation of ARPC, and our study provided a potential therapeutic strategy for AKI.

show abstract

“…Furthermore, activated cytotoxic T cells are known to play an important role in the inflammatory activity and destruction of allograft tissue (9). The increased presence of cytotoxic granules such as granzyme B have been associated with acute rejection (10)(11)(12). Similarly, FoxP3 + T cells [T regulatory cells (Tregs)] have been identified as potential crucial players in inflammatory disease and allograft rejection (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Immune Cell Infiltrate in Chronic-Active Antibody-Mediated Rejection

et al. 2020

View full text Add to dashboard Cite

Background: Little is known about immune cell infiltrate type in the kidney allograft of patients with chronic-active antibody-mediated rejection (c-aABMR). Methods: In this study, multiplex immunofluorescent staining was performed on 20 cases of biopsy-proven c-aABMR. T-cell subsets (CD3, CD8, Foxp3, and granzyme B), macrophages (CD68 and CD163), B cells (CD20), and natural killer cells (CD57) were identified and counted in the glomeruli (cells/glomerulus) and the tubulointerstitial (TI) compartment [cells/high-power field (HPF)]. Results: In the glomerulus, T cells and macrophages were the dominant cell types with a mean of 5.5 CD3 + cells/glomerulus and 4 CD68 + cells/glomerulus. The majority of T cells was CD8 + (62%), and most macrophages were CD68 + CD163 + (68%). The TI compartment showed a mean of 116 CD3 + cells/HPF, of which 54% were CD8 +. Macrophage count was 21.5 cells/HPF with 39% CD68 + CD163 +. CD20 + cells were sporadically present in glomeruli, whereas B-cell aggregates in the TI compartment were frequently observed. Natural killer cells were rarely identified. Remarkably, increased numbers of CD3 + FoxP3 + cells in the TI compartment were associated with decreased graft survival (p = 0.004). Conclusions: Renal allograft biopsies showing c-aABMR show a predominance of infiltrating CD8 + T cells, and increased numbers of interstitial FoxP3 + T cells are associated with inferior allograft survival.

show abstract

Serine Protease Inhibitor-6 Inhibits Granzyme B–Mediated Injury of Renal Tubular Cells and Promotes Renal Allograft Survival

Cited by 13 publications

References 35 publications

Activity-based Protein Profiling Approaches for Transplantation

Activity-based Protein Profiling Approaches for Transplantation

Nephropreventing effect of hypoxia‐inducible factor 1α in a rat model of ischaemic/reperfusion acute kidney injury

Immune Cell Infiltrate in Chronic-Active Antibody-Mediated Rejection

Contact Info

Product

Resources

About