Red blood cell-derived arginase release in hemolytic uremic syndrome
Friberg, Niklas LU
; Arvidsson, Ida
LU
; Tontanahal, Ashmita
LU
; Kristoffersson, Ann-Charlotte
LU
; Gram, Magnus
LU
; Kaplan, Bernard S.
and Karpman, Diana
LU
(2024)
In Journal of Translational Medicine
22(1).
- Abstract
- Background
Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury.
Methods
Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which... (More) - Background
Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury.
Methods
Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann–Whitney test, multiple groups were compared using the Kruskal–Wallis test followed by Dunn’s procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables.
Results
HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis.
Conclusions
Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/75e6e82c-2445-4831-a847-52a5349191f6
- author
- Friberg, Niklas
LU
; Arvidsson, Ida
LU
; Tontanahal, Ashmita
LU
; Kristoffersson, Ann-Charlotte
LU
; Gram, Magnus
LU
; Kaplan, Bernard S.
and Karpman, Diana
LU
- organization
- publishing date
- 2024-01-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Arginase, Hemolytic uremic syndrome, Thrombotic microangiopathy, Nitric oxide, Shiga toxin
- in
- Journal of Translational Medicine
- volume
- 22
- issue
- 1
- article number
- 17
- pages
- 16 pages
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85181467800
- pmid:38178089
- ISSN
- 1479-5876
- DOI
- 10.1186/s12967-023-04824-x
- project
- Arginase and vascular inflammation in the pathogenesis of hemolytic uremic syndrome
- language
- English
- LU publication?
- yes
- id
- 75e6e82c-2445-4831-a847-52a5349191f6
- date added to LUP
- 2024-01-09 12:57:08
- date last changed
- 2024-04-23 02:59:34
@article{75e6e82c-2445-4831-a847-52a5349191f6,
abstract = {{Background<br/><br/>Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury.<br/>Methods<br/><br/>Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann–Whitney test, multiple groups were compared using the Kruskal–Wallis test followed by Dunn’s procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables.<br/>Results<br/><br/>HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis.<br/>Conclusions<br/><br/>Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.}},
author = {{Friberg, Niklas and Arvidsson, Ida and Tontanahal, Ashmita and Kristoffersson, Ann-Charlotte and Gram, Magnus and Kaplan, Bernard S. and Karpman, Diana}},
issn = {{1479-5876}},
keywords = {{Arginase; Hemolytic uremic syndrome; Thrombotic microangiopathy; Nitric oxide; Shiga toxin}},
language = {{eng}},
month = {{01}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Journal of Translational Medicine}},
title = {{Red blood cell-derived arginase release in hemolytic uremic syndrome}},
url = {{http://dx.doi.org/10.1186/s12967-023-04824-x}},
doi = {{10.1186/s12967-023-04824-x}},
volume = {{22}},
year = {{2024}},
}