Red blood cell-derived arginase release in hemolytic uremic syndrome
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 bioava...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04824-x |
| _version_ | 1797362929398448128 |
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| author | Niklas Friberg Ida Arvidsson Ashmita Tontanahal Ann-Charlotte Kristoffersson Magnus Gram Bernard S. Kaplan Diana Karpman |
| author_facet | Niklas Friberg Ida Arvidsson Ashmita Tontanahal Ann-Charlotte Kristoffersson Magnus Gram Bernard S. Kaplan Diana Karpman |
| author_sort | Niklas Friberg |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-08T16:14:29Z |
| format | Article |
| id | doaj.art-8c7d034f43a8444381862106789a69c4 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T16:14:29Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-8c7d034f43a8444381862106789a69c42024-01-07T12:42:04ZengBMCJournal of Translational Medicine1479-58762024-01-0122111610.1186/s12967-023-04824-xRed blood cell-derived arginase release in hemolytic uremic syndromeNiklas Friberg0Ida Arvidsson1Ashmita Tontanahal2Ann-Charlotte Kristoffersson3Magnus Gram4Bernard S. Kaplan5Diana Karpman6Department of Pediatrics, Clinical Sciences Lund, Lund UniversityDepartment of Pediatrics, Clinical Sciences Lund, Lund UniversityDepartment of Pediatrics, Clinical Sciences Lund, Lund UniversityDepartment of Pediatrics, Clinical Sciences Lund, Lund UniversityDepartment of Pediatrics, Clinical Sciences Lund, Lund UniversityDivision of Nephrology, Children’s Hospital of PhiladelphiaDepartment of Pediatrics, Clinical Sciences Lund, Lund UniversityAbstract 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.https://doi.org/10.1186/s12967-023-04824-xArginaseHemolytic uremic syndromeThrombotic microangiopathyNitric oxideShiga toxin |
| spellingShingle | Niklas Friberg Ida Arvidsson Ashmita Tontanahal Ann-Charlotte Kristoffersson Magnus Gram Bernard S. Kaplan Diana Karpman Red blood cell-derived arginase release in hemolytic uremic syndrome Journal of Translational Medicine Arginase Hemolytic uremic syndrome Thrombotic microangiopathy Nitric oxide Shiga toxin |
| title | Red blood cell-derived arginase release in hemolytic uremic syndrome |
| title_full | Red blood cell-derived arginase release in hemolytic uremic syndrome |
| title_fullStr | Red blood cell-derived arginase release in hemolytic uremic syndrome |
| title_full_unstemmed | Red blood cell-derived arginase release in hemolytic uremic syndrome |
| title_short | Red blood cell-derived arginase release in hemolytic uremic syndrome |
| title_sort | red blood cell derived arginase release in hemolytic uremic syndrome |
| topic | Arginase Hemolytic uremic syndrome Thrombotic microangiopathy Nitric oxide Shiga toxin |
| url | https://doi.org/10.1186/s12967-023-04824-x |
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