Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI

Li, Hongmei; Han, Sang Jun; Kim, Mihwa; Cho, Ahyeon; Choi, Y.-J. A.; D’Agati, Vivette D.; Lee, H. Thomas

doi:10.1152/ajprenal.00569.2017

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…We have previously shown that renal I/R injury induced renal proximal tubular PAD4 synthesis and activity (22,49). Our studies linked both renal proximal tubular as well as leukocyte PAD4 to critical roles in ischemic AKI as mice deficient in renal proximal tubular PAD4 as well as leukocytederived PAD4 were protected against ischemic AKI (40).…”

Section: Discussionmentioning

confidence: 60%

Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO

Rabadi

Han

Kim

et al. 2019

American Journal of Physiology-Renal Physiology

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Peptidyl arginine deiminase-4 (PAD4) catalyzes the conversion of peptidylarginine residues to peptidylcitrulline. We have previously shown that kidney ischemia-reperfusion (I/R) injury increases renal proximal tubular PAD4 expression and activity. Furthermore, kidney PAD4 plays a critical role in ischemic acute kidney injury (AKI) by promoting renal tubular inflammation, neutrophil infiltration, and NF-κB activation. However, the mechanisms of PAD4-mediated renal tubular inflammation and NF-κB activation after I/R remain unclear. Here, we show that recombinant PAD4 preferentially citrullinates recombinant IKKγ [also called NF-κB essential modulator (NEMO)] over recombinant IKKα or IKKβ. Consistent with this finding, PAD4 citrullinated renal proximal tubular cell IKKγ and promoted NF-κB activation via IκBα phosphorylation in vitro. NEMO inhibition with a selective NEMO-binding peptide attenuated PAD4-mediated proinflammatory cytokine mRNA induction in HK-2 cells. Moreover, NEMO inhibition did not affect proximal tubular cell survival, proliferation, or apoptosis, unlike global NF-κB inhibition. In vivo, NEMO-binding peptide treatment protected against ischemic AKI. Finally, NEMO-binding peptide attenuated recombinant PAD4-mediated exacerbation of ischemic AKI, renal tubular inflammation, and apoptosis. Taken together, our results show that PAD4 exacerbates ischemic AKI and inflammation by promoting renal tubular NF-κB activity and inflammation via NEMO citrullination. Targeting NEMO activation may serve as a potential therapy for this devastating clinical problem.

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Section: Discussionmentioning

confidence: 60%

Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO

Rabadi

Han

Kim

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Further studies are required to explore the function of PAD4 in human lupus nephritis. In addition, the role of PAD4 in neutrophils and renal proximal tubular cells has been reported in acute kidney injury (61). Therefore, future studies with conditional KO mice specific for either neutrophils or tubular cells are also needed to dissect the cell-specific effect of PAD4 in lupus nephritis.…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice

et al. 2020

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Peptidylarginine deiminase 4 (PAD4), encoded by PADI4, plays critical roles in the immune system; however, its contribution to the pathogenesis of lupus nephritis remains controversial. The pathological roles of PAD4 were investigated in lupus model mice. An imiquimod (IMQ)-induced lupus model was analyzed in wild-type (WT) and Padi4-knockout (KO) mice. Proteinuria, serum anti-double stranded DNA (anti-dsDNA) antibody, and renal infiltrated cells were evaluated. Neutrophil migration and adhesion were assessed using adoptive transfer and adhesion assay. PAD4-regulated pathways were identified by RNA-sequencing of Padi4 KO neutrophils. Padi4 KO mice exhibited significant improvements in proteinuria progression compared with WT mice, whereas, serum anti-dsDNA antibody and immune complex deposition in the glomeruli showed no difference between both mice strains. Padi4 KO mice showed decreased neutrophil infiltration in the kidneys. Adoptively transferred Padi4 KO neutrophils showed decreased migration to the kidneys of IMQ-treated WT mice, and adhesion to ICAM-1 was impaired in Padi4 KO neutrophils. Padi4 KO neutrophils exhibited reduced upregulation of p38 mitogen-activated protein kinase (MAPK) pathways. Toll-like receptor 7 (TLR7)-primed Padi4 KO neutrophils demonstrated reduced phosphorylation of p38 MAPK and lower expression of JNK-associated leucine zipper protein (JLP), a p38 MAPK scaffold protein. Neutrophils from heterozygous Jlp KO mice showed impaired adhesion to ICAM-1 and decreased migration to the kidneys of IMQ-treated WT mice. These results indicated a pivotal role of PAD4-p38 MAPK pathway in renal neutrophil infiltration in TLR7 agonist-induced lupus nephritis, and the importance of neutrophil-mediated kidney inflammation. Inhibition of the PAD4-p38 MAPK pathway may help in formulating a novel therapeutic strategy against lupus nephritis.

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“…M2-activated macrophages are comprised of wound healing and immunoregulatory macrophages (Shapouri-Moghaddam et al 2018). M2 macrophages secrete resolvins, lipoxins, transforming growth factor beta, and matrix metalloproteinases to cleave chemokines and chemoattractants and suppress the inflammatory response, contribute to tissue repair, remodeling, vasculogenesis, and retain homeostasis (Han et al 2018; Shapouri-Moghaddam et al 2018). M-CSF is a hematopoietic growth factor responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages (Radi et al 2011).…”

Section: The Immune and Renal Systems Network And Cross Talksmentioning

confidence: 99%

“…Peptidylarginine deiminase-4 (PAD4) plays a critical role in ischemic AKI in mice by promoting renal tubular inflammation and neutrophil infiltration (H. Li et al 2018). Renal proximal tubular cell in PAD4 deficient mice had profoundly reduced renal tubular apoptosis (H. Li et al 2018). Although neutrophil infiltration can be noted in the kidney following ischemic injury in I/R injury animal models (Nemoto et al 2001; Tadagavadi et al 2015) and human biopsies of AKI patients (Solez, Morel–Maroger, and Sraer 1979; Friedewald and Rabb 2004), neutrophil depletion and neutropenia in rats did not protect against ischemic injury (Paller et al 1989).…”

Section: The Immune and Renal Systems Network And Cross Talksmentioning

confidence: 99%

“…In a mouse model of cisplatin-induced AKI, neutrophil infiltration into the kidney and the expression of IL-1b, IL-18, and IL-6 were increased; however, blocking either neutrophil infiltration or these cytokines did not prevent cisplatin-induced AKI (Faubel et al 2007). Peptidylarginine deiminase-4 (PAD4) plays a critical role in ischemic AKI in mice by promoting renal tubular inflammation and neutrophil infiltration (H. Li et al 2018). Renal proximal tubular cell in PAD4 deficient mice had profoundly reduced renal tubular apoptosis (H. Li et al 2018).…”

Section: Neutrophils and Akimentioning

confidence: 99%

See 1 more Smart Citation

Immunopathogenesis of Acute Kidney Injury

Radi

2018

Toxicol Pathol

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Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

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Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI

Cited by 12 publications

References 42 publications

Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO

Peptidyl arginine deiminase-4 exacerbates ischemic AKI by finding NEMO

Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice

Immunopathogenesis of Acute Kidney Injury

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