scholarly journals Macrophage Heterogeneity in Kidney Injury and Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Wen ◽  
Hong-Ru Yan ◽  
Bin Wang ◽  
Bi-Cheng Liu
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Kidney Diseases ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
Kidney Fibrosis ◽  
Functional Changes ◽  
Monocyte Subpopulations ◽  
Macrophage Accumulation

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C+ monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases.

SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function

2021 ◽  
Vol 14 (672) ◽  
pp. eabb4282 ◽  
Author(s):  
Sayyid Raza ◽  
Elliot Jokl ◽  
James Pritchett ◽  
Katherine Martin ◽  
Kim Su ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Actin Polymerization ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Pharmacological Intervention ◽  
Kidney Fibrosis ◽  
Genome Wide ◽  
Vitro Model ◽  
Sustained Activation

Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitro model of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required for multiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation of the mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Chul Kim ◽  
Junghun Lee ◽  
Jung Nam An ◽  
Jin Hyuk Kim ◽  
Young-Wook Choi ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Active Form ◽  
Kidney Injury ◽  
Biologically Active ◽  
Kidney Fibrosis ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
A Cell ◽  
Masson Trichrome Staining ◽  
Hepatocyte Growth

Abstract Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.

scholarly journals Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

2011 ◽  
Vol 121 (9) ◽  
pp. 367-387 ◽  
Author(s):  
Mark L. Hanke ◽  
Tammy Kielian
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Microbial Pathogens ◽  
Type I ◽  
Toll Like Receptors ◽  
Microbial Infection ◽  
Cns Disorders ◽  
The Brain ◽  
Tlr Signalling

The discovery of mammalian TLRs (Toll-like receptors), first identified in 1997 based on their homology with Drosophila Toll, greatly altered our understanding of how the innate immune system recognizes and responds to diverse microbial pathogens. TLRs are evolutionarily conserved type I transmembrane proteins expressed in both immune and non-immune cells, and are typified by N-terminal leucine-rich repeats and a highly conserved C-terminal domain termed the TIR [Toll/interleukin (IL)-1 receptor] domain. Upon stimulation with their cognate ligands, TLR signalling elicits the production of cytokines, enzymes and other inflammatory mediators that can have an impact on several aspects of CNS (central nervous system) homoeostasis and pathology. For example, TLR signalling plays a crucial role in initiating host defence responses during CNS microbial infection. Furthermore, TLRs are targets for many adjuvants which help shape pathogen-specific adaptive immune responses in addition to triggering innate immunity. Our knowledge of TLR expression and function in the CNS has greatly expanded over the last decade, with new data revealing that TLRs also have an impact on non-infectious CNS diseases/injury. In particular, TLRs recognize a number of endogenous molecules liberated from damaged tissues and, as such, influence inflammatory responses during tissue injury and autoimmunity. In addition, recent studies have implicated TLR involvement during neurogenesis, and learning and memory in the absence of any underlying infectious aetiology. Owing to their presence and immune-regulatory role within the brain, TLRs represent an attractive therapeutic target for numerous CNS disorders and infectious diseases. However, it is clear that TLRs can exert either beneficial or detrimental effects in the CNS, which probably depend on the context of tissue homoeostasis or pathology. Therefore any potential therapeutic manipulation of TLRs will require an understanding of the signals governing specific CNS disorders to achieve tailored therapy.

scholarly journals Therapeutic Potential of Annexin A1 Modulation in Kidney and Cardiovascular Disorders

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3420
Author(s):  
Mahmood S. Mozaffari
Keyword(s):  
Cardiovascular System ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Stone Formation ◽  
Kidney Injury ◽  
Cardiovascular Disorders ◽  
Annexin A1 ◽  
Drug Induced ◽  
Vascular Abnormalities ◽  
Functional Features

Renal and cardiovascular disorders are very prevalent and associated with significant morbidity and mortality. Among diverse pathogenic mechanisms, the dysregulation of immune and inflammatory responses plays an essential role in such disorders. Consequently, the discovery of Annexin A1, as a glucocorticoid-inducible anti-inflammatory protein, has fueled investigation of its role in renal and cardiovascular pathologies. Indeed, with respect to the kidney, its role has been examined in diverse renal pathologies, including acute kidney injury, diabetic nephropathy, immune-mediated nephropathy, drug-induced kidney injury, kidney stone formation, and renal cancer. Regarding the cardiovascular system, major areas of investigation include the role of Annexin A1 in vascular abnormalities, atherosclerosis, and myocardial infarction. Thus, this review briefly describes major structural and functional features of Annexin A1 followed by a review of its role in pathologies of the kidney and the cardiovascular system, as well as the therapeutic potential of its modulation for such disorders.

scholarly journals Mesenchymal Stem Cells—Potential Applications in Kidney Diseases

2019 ◽  
Vol 20 (10) ◽  
pp. 2462 ◽  
Author(s):  
Benjamin Bochon ◽  
Magdalena Kozubska ◽  
Grzegorz Surygała ◽  
Agnieszka Witkowska ◽  
Roman Kuźniewicz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Clinical Effects ◽  
Potential Applications ◽  
The Subject ◽  
Subcutaneous Adipose

Mesenchymal stem cells constitute a pool of cells present throughout the lifetime in numerous niches, characteristic of unlimited replication potential and the ability to differentiate into mature cells of mesodermal tissues in vitro. The therapeutic potential of these cells is, however, primarily associated with their capabilities of inhibiting inflammation and initiating tissue regeneration. Owing to these properties, mesenchymal stem cells (derived from the bone marrow, subcutaneous adipose tissue, and increasingly urine) are the subject of research in the settings of kidney diseases in which inflammation plays the key role. The most advanced studies, with the first clinical trials, apply to ischemic acute kidney injury, renal transplantation, lupus and diabetic nephropathies, in which beneficial clinical effects of cells themselves, as well as their culture medium, were observed. The study findings imply that mesenchymal stem cells act predominantly through secreted factors, including, above all, microRNAs contained within extracellular vesicles. Research over the coming years will focus on this secretome as a possible therapeutic agent void of the potential carcinogenicity of the cells.

scholarly journals Potential and Therapeutic Efficacy of Cell-based Therapy Using Mesenchymal Stem Cells for Acute/chronic Kidney Disease

2019 ◽  
Vol 20 (7) ◽  
pp. 1619 ◽  
Author(s):  
Chul Yun ◽  
Sang Lee
Keyword(s):  
Chronic Kidney Disease ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Kidney Disease ◽  
Therapeutic Efficacy ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Kidney Diseases ◽  
Diverse Range ◽  
Cell Based Therapy

Kidney disease can be either acute kidney injury (AKI) or chronic kidney disease (CKD) and it can lead to the development of functional organ failure. Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have immunomodulatory effects to assist in the recovery from tissue injury and the inhibition of inflammation. Numerous studies have investigated the feasibility, safety, and efficacy of MSC-based therapies for kidney disease. Although the exact mechanism of MSC-based therapy remains uncertain, their therapeutic value in the treatment of a diverse range of kidney diseases has been studied in clinical trials. The use of MSCs is a promising therapeutic strategy for both acute and chronic kidney disease. The mechanism underlying the effects of MSCs on survival rate after transplantation and functional repair of damaged tissue is still ambiguous. The paracrine effects of MSCs on renal recovery, optimization of the microenvironment for cell survival, and control of inflammatory responses are thought to be related to their interaction with the damaged kidney environment. This review discusses recent experimental and clinical findings related to kidney disease, with a focus on the role of MSCs in kidney disease recovery, differentiation, and microenvironment. The therapeutic efficacy and current applications of MSC-based kidney disease therapies are also discussed.

Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation

2021 ◽  
pp. ASN.2020071010
Author(s):  
Kensuke Sasaki ◽  
Andrew S. Terker ◽  
Yu Pan ◽  
Zhilian Li ◽  
Shirong Cao ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
Significant Inhibition ◽  
Macrophage Infiltration ◽  
Wild Type ◽  
Regulatory Factor ◽  
Macrophage Cell ◽  
Kidney Fibrosis ◽  
M2 Phenotype

BackgroundAKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear.MethodsWe used mice with myeloid or macrophage cell–specific deletion of Irf4 (MΦ Irf4−/−) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI.ResultsSurprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ Irf4−/− mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4−/− BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4−/− mice or in wild-type mice with inhibition of AKT activity.ConclusionsDeletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

scholarly journals Vascular Permeability: Regulation Pathways and Role in Kidney Diseases

Nephron ◽  
2021 ◽  
pp. 1-14
Author(s):  
Anxiang Cai ◽  
Christos Chatziantoniou ◽  
Amélie Calmont
Keyword(s):  
Kidney Disease ◽  
Vascular Permeability ◽  
Tissue Injury ◽  
Kidney Diseases ◽  
Platelet Activating Factor ◽  
Kidney Injury ◽  
Angiogenic Factors ◽  
Inflammatory Factors ◽  
Fundamental Aspect ◽  
Vascular Endothelial

Background: Vascular permeability (VP) is a fundamental aspect of vascular biology. A growing number of studies have revealed that many signalling pathways govern VP in both physiological and pathophysiological conditions. Furthermore, emerging evidence identifies VP alteration as a pivotal pathogenic factor in acute kidney injury, chronic kidney disease, diabetic kidney disease, and other proteinuric diseases. Therefore, perceiving the connections between these pathways and the aetiology of kidney disease is an important task as such knowledge may trigger the development of novel therapeutic or preventive medical approaches. In this regard, the discussion summarizing VP-regulating pathways and associating them with kidney diseases is highly warranted. Summary: Major pathways of VP regulation comprise angiogenic factors including vascular endothelial growth factor/VEGFR, angiopoietin/Tie, and class 3 semaphorin/neuropilin and inflammatory factors including histamine, platelet-activating factor, and leukocyte extravasation. These pathways mainly act on vascular endothelial cadherin to modulate adherens junctions of endothelial cells (ECs), thereby augmenting VP via the paracellular pathway. Elevated VP in diverse kidney diseases involves EC apoptosis, imbalanced regulatory factors, and many other pathophysiological events, which in turn exacerbates renal structural and functional disorders. Measures improving VP effectively ameliorate the diseased kidney in terms of tissue injury, endothelial dysfunction, kidney function, and long-term prognosis. Key Messages: (1) Angiogenic factors, inflammatory factors, and adhesion molecules represent major pathways that regulate VP. (2) Vascular hyperpermeability links various pathophysiological processes and plays detrimental roles in multiple kidney diseases.

scholarly journals The Role of Macrophages in Kidney Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoling Wang ◽  
Jianwei Chen ◽  
Jun Xu ◽  
Jun Xie ◽  
David C. H. Harris ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Functional Diversity ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Phenotypic Heterogeneity ◽  
Kidney Fibrosis ◽  
Direct Contribution ◽  
Anti Inflammatory

The phenotypic heterogeneity and functional diversity of macrophages confer on them complexed roles in the development and progression of kidney diseases. After kidney injury, bone marrow-derived monocytes are rapidly recruited to the glomerulus and tubulointerstitium. They are activated and differentiated on site into pro-inflammatory M1 macrophages, which initiate Th1-type adaptive immune responses and damage normal tissues. In contrast, anti-inflammatory M2 macrophages induce Th2-type immune responses, secrete large amounts of TGF-β and anti-inflammatory cytokines, transform into αSMA+ myofibroblasts in injured kidney, inhibit immune responses, and promote wound healing and tissue fibrosis. Previous studies on the role of macrophages in kidney fibrosis were mainly focused on inflammation-associated injury and injury repair. Apart from macrophage-secreted profibrotic cytokines, such as TGF-β, evidence for a direct contribution of macrophages to kidney fibrosis is lacking. However, under inflammatory conditions, Wnt ligands are derived mainly from macrophages and Wnt signaling is central in the network of multiple profibrotic pathways. Largely underinvestigated are the direct contribution of macrophages to profibrotic signaling pathways, macrophage phenotypic heterogeneity and functional diversity in relation to kidney fibrosis, and on their cross-talk with other cells in profibrotic signaling networks that cause fibrosis. Here we aim to provide an overview on the roles of macrophage phenotypic and functional diversity in their contribution to pro-fibrotic signaling pathways, and on the therapeutic potential of targeting macrophages for the treatment of kidney fibrosis.

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