IL-17A blockade or deficiency does not affect progressive renal fibrosis following renal ischaemia reperfusion injury in mice

Thorenz, Anja; Völker, Nicole; Bräsen, Jan Hinrich; Chen, Rongjun; Jang, Mi-Sun; Rong, Song; Haller, Hermann; Kirsch, Torsten; Vieten, Gertrud; Klemann, Christian; Gueler, Faikah

doi:10.1111/jphp.12747

Cited by 13 publications

(8 citation statements)

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“…Our finding that IL‐17A deficiency did not reduce renal fibrosis in CKD is, however, compatible with recent data from Thorenz et al . who reported that IL‐17A deficient mice were not protected against renal fibrosis induced by ischaemia/reperfusion injury (Thorenz et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…For example, cisplatin-induced renal injury was markedly decreased in RAG-1 deficient mice (Nozaki et al, 2011) showing that the adaptive immune system aggravates nephrotoxicity induced by cisplatin. IL-17A producing cells initiate, perpetuate and sustain inflammatory processes by inducing proinflammatory cytokines and chemokines and recruiting other inflammatory cells and orchestrating tissue inflammation (Thorenz et al, 2017). Strikingly, neither deficiency of the adaptive immune system nor of IL-17A affected the induction and course of progressive renal injury.…”

Section: Discussionmentioning

confidence: 99%

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Adaptive immunity and IL‐17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice

Rosendahl

Kabiri

Bode

et al. 2018

British J Pharmacology

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Background and Purpose The adaptive immune response and IL‐17A contribute to renal damage in several experimental models of renal injury. Experimental Approach To evaluate the role of the adaptive immune response, 5/6 nephrectomy was performed in wildtype DBA/1J mice and in recombination‐activating gene‐1 (RAG‐1) deficient mice that lack B and T‐cells. To assess the role of IL‐17A, we carried out 5/6 nephrectomy in IL‐17A deficient mice. Flow cytometric analysis, immunohistochemistry and RT‐PCR were used. Key Results Infiltration of CD3+ T‐cells in the remnant kidney was increased after 5/6 nephrectomy in wildtype mice, along with a robust induction of IL‐17A production in CD4+ T and γδ T‐cells. After 5/6 nephrectomy, wildtype mice developed albuminuria in the nephrotic range over 10 weeks. This was accompanied by severe glomerular sclerosis and tubulointerstitial injury, and as well as renal mRNA expression of markers of inflammation and fibrosis (the chemokine CCL2, plasminogen activator inhibitor‐1; PAI‐1 and neutrophil gelatinase‐associated lipocalin; NGAL). Unexpectedly, RAG‐1 deficient mice and IL‐17A deficient mice developed renal injury, similar to that in wildtype mice. No differences were found for albuminuria, glomerular sclerosis, tubulointerstitial injury and mRNA expression of CCL2, PAI‐1 and NGAL. Mortality did not differ between the three groups. Conclusions and Implications Numbers of CD3+ T‐cells and IL‐17A+ lymphocytes infiltrating the kidney were increased after 5/6 nephrectomy. In contrast to other experimental models of renal injury, genetic deficiency of the adaptive immune system or of IL‐17A did not attenuate induction or progression of chronic kidney disease after 5/6 nephrectomy. Linked Articles This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Adaptive immunity and IL‐17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice

Rosendahl

Kabiri

Bode

et al. 2018

British J Pharmacology

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“…Nevertheless, some other studies raised doubts due to blockade or deficiency of IL-17A having no beneficial effect on preventing renal fibrosis progression following severe IRI. The different severity of IRI might account for the contradictory conclusions (Thorenz et al, 2017 ; Rosendahl et al, 2019 ). Thus, whether the inhibitors of IL-17 cytokine family can be clinically applicated remains to be explored.…”

Section: Lymphocytes Mediate Aki and Ckd: Diversity And Mechanismsmentioning

confidence: 99%

Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

2021

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Background: Acute kidney injury (AKI) remains a major global public health concern due to its high morbidity and mortality. The progression from AKI to chronic kidney disease (CKD) makes it a scientific problem to be solved. However, it is with lack of effective treatments.Summary: Both innate and adaptive immune systems participate in the inflammatory process during AKI, and excessive or dysregulated immune responses play a pathogenic role in renal fibrosis, which is an important hallmark of CKD. Studies on the pathogenesis of AKI and CKD have clarified that renal injury induces the production of various chemokines by renal parenchyma cells or resident immune cells, which recruits multiple-subtype lymphocytes in circulation. Some infiltrated lymphocytes exacerbate injury by proinflammatory cytokine production, cytotoxicity, and interaction with renal resident cells, which constructs the inflammatory environment and induces further injury, even death of renal parenchyma cells. Others promote tissue repair by producing protective cytokines. In this review, we outline the diversity of these lymphocytes and their mechanisms to regulate the whole pathogenic stages of AKI and CKD; discuss the chronological responses and the plasticity of lymphocytes related to AKI and CKD progression; and introduce the potential therapies targeting lymphocytes of AKI and CKD, including the interventions of chemokines, cytokines, and lymphocyte frequency regulation in vivo, adaptive transfer of ex-expanded lymphocytes, and the treatments of gut microbiota or metabolite regulations based on gut-kidney axis.Key Message: In the process of AKI and CKD, T helper (Th) cells, innate, and innate-like lymphocytes exert mainly pathogenic roles, while double-negative T (DNT) cells and regulatory T cells (Tregs) are confirmed to be protective. Understanding the mechanisms by which lymphocytes mediate renal injury and renal fibrosis is necessary to promote the development of specific therapeutic strategies to protect from AKI and prevent the progression of CKD.

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“…About 70% of the renal tissue was used for leukocyte isolation as described previously. 21 Tissues were homogenized with a gentleMACS dissociator (Miltenyi Biotec, USA) according to the manufacturer's instructions. Digestion with Collagenase II (500 U/ml, Worthington, USA) was performed before and after homogenization for 20 min at 37°C.…”

Section: Flow Cytometry To Estimate Nav13-expressing Neutrophilsmentioning

confidence: 99%

Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro

et al. 2018

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Background Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. Methods Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. Results Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. Conclusions Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine.

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IL-17A blockade or deficiency does not affect progressive renal fibrosis following renal ischaemia reperfusion injury in mice

Abstract: Despite the effects of IL-17 in other inflammation models, neither genetic IL-17A deficiency nor treatment with an IL-17A blocking antibody attenuated IRI and progression to CKD. We conclude that in severe renal IRI IL-17A is not crucially involved in disease progression.

Cited by 13 publications

References 40 publications

Adaptive immunity and IL‐17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice

Adaptive immunity and IL‐17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice

Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro

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