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Special Issue "Kidney Inflammation, Injury and Regeneration"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 29 November 2019.

Special Issue Editors

Prof. Dr. Patrick C. Baer
E-Mail Website
Guest Editor
Nephrology, Department of Internal Medicine, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
Interests: acute kidney injury; renal tubular cells; in vitro models; in vivo models; kidney regeneration; epithelial cells; mesenchymal stem cells; adipose-derived stromal/stem cells; cell differentiation; extracellular vesicles
Special Issues and Collections in MDPI journals
Prof. Dr. Helmut Geiger
E-Mail Website
Guest Editor
Nephrology, Department of Internal Medicine, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
Interests: renal diseases; acute kidney injury; chronic kidney; hypertension; dialysis; renal transplantion, renal regeneration
Dr. Benjamin Koch
E-Mail Website
Guest Editor
Nephrology, Department of Internal Medicine, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
Interests: transcriptomics in acute and chronic kidney injury; novel blood filtration devices in viral and bacterial sepsis; in vitro models of viral and bacterial sepsis; donor specific antibodies in renal transplantation; extracellular vesicles, renal regeneration

Special Issue Information

Dear Colleagues,

Acute kidney injury (AKI) is still associated with high morbidity and mortality incidence rates, and also bears an elevated risk of chronic kidney disease in the sequel. Whereas the kidney has a remarkable capacity for regeneration after injury and may recover completely depending on the type of renal lesions, the options for clinical intervention are restricted to fluid management and extracorporeal kidney support. The development of novel therapies to prevent AKI, to improve renal regeneration capacity after AKI and to preserve renal function—in both the short- and long-term—is urgently needed.

This Special Issue will include papers investigating the pathological mechanisms of renal inflammation and AKI, and diagnostics using new biomarkers. Furthermore, experimental in vitro and in vivo studies and clinical studies examining potential new approaches to attenuate kidney dysfunction are welcome.

This Special Issue welcomes original research and review papers. Potential topics include, but are not limited to, the following:

  1. Molecular mechanisms of kidney inflammation and epithelial cell injury
  2. Acute kidney injury (AKI) – Pathological mechanisms and new biomarkers
  3. Kidney inflammation and injury: Transcriptomics and proteomics
  4. In vitro models simulating tubular inflammation, injury and regeneration
  5. In vivo AKI models
  6. Investigations to preserve renal function using stem cells or their derivates

Dr. med. Benjamin Koch
Prof. Dr. med. Helmut Geiger
Prof. Dr. phil. nat. Patrick C. Baer
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Renal inflammation
  • Acute kidney injury
  • Pathological mechanisms
  • Renal tubular epithelial cells
  • Biomarkers
  • Transcriptomics
  • Proteomics
  • Epithelial recovery
  • Organ regeneration
  • Tissue engineering
  • Regenerative medicine

Published Papers (24 papers)

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Research

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Open AccessArticle
Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice
Int. J. Mol. Sci. 2019, 20(19), 4680; https://doi.org/10.3390/ijms20194680 - 21 Sep 2019
Abstract
Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) [...] Read more.
Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessCommunication
Noninvasive Urinary Monitoring of Progression in IgA Nephropathy
Int. J. Mol. Sci. 2019, 20(18), 4463; https://doi.org/10.3390/ijms20184463 - 10 Sep 2019
Abstract
Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic [...] Read more.
Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Targeting ROS and cPLA2/COX2 Expressions Ameliorated Renal Damage in Obese Mice with Endotoxemia
Int. J. Mol. Sci. 2019, 20(18), 4393; https://doi.org/10.3390/ijms20184393 - 06 Sep 2019
Abstract
Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice [...] Read more.
Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice (HF group) were injected with lipopolysaccharide (LPS) to yield the obese kidney fibrosis–metabolic endotoxemia mouse model (HL group). Therapeutic effects of ROS, cytosolic phospholipases A2 (cPLA2) and cyclooxygenase-2 (COX-2) inhibitors were analyzed with a quantitative comparison of immunohistochemistry stains and morphometric approach in the tubulointerstitium of different groups. Compared with basal and HF groups, the HL group exhibited the most prominent obese kidney fibrosis, tubular epithelial lipid vacuoles, and lymphocyte infiltration in the tubulointerstitium. Furthermore, inhibitors of nonspecific ROS, cPLA2 and COX-2 ameliorated the above renal damages. Notably, the ROS-inhibitor-treated group ameliorated not only oxidative injury but also the expression of cPLA2 and COX-2, indicating that ROS functions as the upstream signaling molecule in the inflammatory cascade of obese kidney fibrosis. ROS acts as a key messenger in the signaling transduction of obese kidney fibrosis, activating downstream cPLA2 and COX-2. The given antioxidant treatment ameliorates obese kidney fibrosis resulting from a combined high-fat diet and LPS—ROS could serve as a potential therapeutic target of obese kidney fibrosis with metabolic endotoxemia. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling
Int. J. Mol. Sci. 2019, 20(15), 3682; https://doi.org/10.3390/ijms20153682 - 27 Jul 2019
Abstract
During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly [...] Read more.
During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection
Int. J. Mol. Sci. 2019, 20(10), 2552; https://doi.org/10.3390/ijms20102552 - 24 May 2019
Abstract
The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and [...] Read more.
The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Renal Regenerative Potential of Extracellular Vesicles Derived from miRNA-Engineered Mesenchymal Stromal Cells
Int. J. Mol. Sci. 2019, 20(10), 2381; https://doi.org/10.3390/ijms20102381 - 14 May 2019
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of [...] Read more.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of EVs and are a promising target for therapeutic interventions. The aim of this study was to increase the content of specific miRNAs in EVs that are known to be involved in the pro-regenerative effect of EVs, and to assess the capacity of modified EVs to contribute to renal regeneration in in vivo models with acute kidney injuries. To this purpose, MSCs were transiently transfected with specific miRNA mimics by electroporation. Molecular analyses showed that, after transfection, MSCs and derived EVs were efficiently enriched in the selected miRNAs. In vitro and in vivo experiments indicated that EVs engineered with miRNAs maintained their pro-regenerative effects. Of relevance, engineered EVs were more effective than EVs derived from naïve MSCs when used at suboptimal doses. This suggests the potential use of a low amount of EVs (82.5 × 106) to obtain the renal regenerative effect. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Contribution of Inflammatory Cytokine Interleukin-18 Genotypes to Renal Cell Carcinoma
Int. J. Mol. Sci. 2019, 20(7), 1563; https://doi.org/10.3390/ijms20071563 - 28 Mar 2019
Abstract
Interleukin-18 (IL-18) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of IL-18 genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of IL-18 [...] Read more.
Interleukin-18 (IL-18) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of IL-18 genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of IL-18 -656 (A/C), -607 (A/C), and -137 (G/C). Moreover, we analyzed their interactions with smoking, alcohol drinking, hypertension, and diabetes status. The results showed an association of the AC and CC genotypes of IL-18 −607 with a significant decrease in the risk of RCC compared with the AA genotype (odds ratio (OR) = 0.44 and 0.35, 95% confidence interval (CI) = 0.27–0.72 and 0.18–0.66, p = 0.0008 and 0.0010, respectively). Furthermore, a significantly lower frequency of the C allele at -607 was observed in the RCC group (35.3% vs. 49.8%; OR = 0.53; 95% CI = 0.35–0.71, p = 0.0003). However, IL-18 -656 and -137 did not exhibit a likewise differential distribution of these genotypes between the control and case groups. Stratifying the population according to smoking, alcohol drinking, hypertension, and diabetes status revealed a different distribution of IL-18 -607 genotypes among non-smokers, non-drinkers, and patients without diabetes, but not among smokers, drinkers, or patients with diabetes. These findings suggest that IL-18 -607 genotypes may play a role in the etiology and progression of RCC in Taiwan and may serve as a useful biomarker for early detection. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Change in Renal Glomerular Collagens and Glomerular Filtration Barrier-Related Proteins in a Dextran Sulfate Sodium-Induced Colitis Mouse Model
Int. J. Mol. Sci. 2019, 20(6), 1458; https://doi.org/10.3390/ijms20061458 - 22 Mar 2019
Abstract
Renal disease is not rare among patients with inflammatory bowel disease (IBD) and is gaining interest as a target of research. However, related changes in glomerular structural have rarely been investigated. This study was aimed at clarifying the changes in collagens and glomerular [...] Read more.
Renal disease is not rare among patients with inflammatory bowel disease (IBD) and is gaining interest as a target of research. However, related changes in glomerular structural have rarely been investigated. This study was aimed at clarifying the changes in collagens and glomerular filtration barrier (GFB)-related proteins of glomeruli in a dextran sulfate sodium (DSS)-induced colitis mouse model. Acute colitis was induced by administering 3.5% DSS in Slc:ICR strain mice for eight days. Histological changes to glomeruli were examined by periodic acid-Schiff (PAS) and Masson’s trichrome staining. Expressions of glomerular collagens and GFB-related proteins were analyzed by immunofluorescent staining and Western blot analysis. DSS-colitis mice showed an elevated disease activity index (DAI), colon shortening, massive cellular infiltration and colon damage, confirming that DSS-colitis mice can be used as an IBD animal model. DSS-colitis mice showed increased glycoprotein and collagen deposition in glomeruli. Interestingly, we observed significant changes in glomerular collagens, including a decrease in type IV collagen, and an increment in type I and type V collagens. Moreover, declined GFB-related proteins expressions were detected, including synaptopodin, podocalyxin, nephrin and VE-cadherin. These results suggest that renal disease in DSS-colitis mice might be associated with changes in glomerular collagens and GFB-related proteins. These findings are important for further elucidation of the clinical pathological mechanisms underlying IBD-associated renal disease. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessArticle
Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis
Int. J. Mol. Sci. 2019, 20(3), 519; https://doi.org/10.3390/ijms20030519 - 26 Jan 2019
Cited by 1
Abstract
Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. [...] Read more.
Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Review

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Open AccessReview
Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View
Int. J. Mol. Sci. 2019, 20(19), 4941; https://doi.org/10.3390/ijms20194941 - 06 Oct 2019
Abstract
Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, [...] Read more.
Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Arachidonic Acid Metabolism and Kidney Inflammation
Int. J. Mol. Sci. 2019, 20(15), 3683; https://doi.org/10.3390/ijms20153683 - 27 Jul 2019
Abstract
As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic [...] Read more.
As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA2 and leukotriene B4 (LTB4) results in inflammatory damage to the kidney. Moreover, the LTB4-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Efficacy of Polyunsaturated Fatty Acids on Inflammatory Markers in Patients Undergoing Dialysis: A Systematic Review with Network Meta-Analysis of Randomized Clinical Trials
Int. J. Mol. Sci. 2019, 20(15), 3645; https://doi.org/10.3390/ijms20153645 - 25 Jul 2019
Abstract
The effects of polyunsaturated fatty acids (PUFAs) on inflammatory markers among patients receiving dialysis have been discussed for a long time, but previous syntheses made controversial conclusion because of highly conceptual heterogeneity in their synthesis. Thus, to further understanding of this topic, we [...] Read more.
The effects of polyunsaturated fatty acids (PUFAs) on inflammatory markers among patients receiving dialysis have been discussed for a long time, but previous syntheses made controversial conclusion because of highly conceptual heterogeneity in their synthesis. Thus, to further understanding of this topic, we comprehensively gathered relevant randomized clinical trials (RCTs) before April 2019, and two authors independently extracted data of C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) for conducting network meta-analysis. Eighteen eligible RCTs with 962 patients undergoing dialysis were included in our study. The result showed that with placebo as the reference, PUFAs was the only treatment showing significantly lower CRP (weighted mean difference (WMD): −0.37, 95% confidence interval (CI): −0.07 to −0.68), but the CRP in PUFAs group was not significantly lower than vitamin E, PUFAs plus vitamin E, or medium-chain triglyceride. Although no significant changes were noted for hs-CRP and IL-6 levels, PUFAs showed the best ranking among treatments according to surface under the cumulative ranking. Therefore, PUFAs could be a protective option for patients receiving dialysis in clinical practice. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Cell Death in the Kidney
Int. J. Mol. Sci. 2019, 20(14), 3598; https://doi.org/10.3390/ijms20143598 - 23 Jul 2019
Abstract
Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the [...] Read more.
Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury
Int. J. Mol. Sci. 2019, 20(14), 3529; https://doi.org/10.3390/ijms20143529 - 19 Jul 2019
Abstract
Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular [...] Read more.
Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease
Int. J. Mol. Sci. 2019, 20(14), 3393; https://doi.org/10.3390/ijms20143393 - 10 Jul 2019
Cited by 1
Abstract
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress [...] Read more.
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Long Non-Coding RNAs in Kidney Disease
Int. J. Mol. Sci. 2019, 20(13), 3276; https://doi.org/10.3390/ijms20133276 - 03 Jul 2019
Abstract
Non-coding RNA species contribute more than 90% of all transcripts and have gained increasing attention in the last decade. One of the most recent members of this group are long non-coding RNAs (lncRNAs) which are characterized by a length of more than 200 [...] Read more.
Non-coding RNA species contribute more than 90% of all transcripts and have gained increasing attention in the last decade. One of the most recent members of this group are long non-coding RNAs (lncRNAs) which are characterized by a length of more than 200 nucleotides and a lack of coding potential. However, in contrast to this simple definition, lncRNAs are heterogenous regarding their molecular function—including the modulation of small RNA and protein function, guidance of epigenetic modifications and a role as enhancer RNAs. Furthermore, they show a highly tissue-specific expression pattern. These aspects already point towards an important role in cellular biology and imply lncRNAs as players in development, health and disease. This view has been confirmed by numerous publications from different fields in the last years and has raised the question as to whether lncRNAs may be future therapeutic targets in human disease. Here, we provide a concise overview of the current knowledge on lncRNAs in both glomerular and tubulointerstitial kidney disease. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Salt Inducible Kinase Signaling Networks: Implications for Acute Kidney Injury and Therapeutic Potential
Int. J. Mol. Sci. 2019, 20(13), 3219; https://doi.org/10.3390/ijms20133219 - 30 Jun 2019
Abstract
A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The [...] Read more.
A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The SIK1 network is activated in the RPT following an increase in intracellular Na+ (Na+in), resulting in an increase in Na,K-ATPase activity, in addition to the phosphorylation of Class IIa Histone Deacetylases (HDACs). In addition, activated SIKs repress transcriptional regulation mediated by the interaction between cAMP Regulatory Element Binding Protein (CREB) and CREB Regulated Transcriptional Coactivators (CRTCs). Through their transcriptional effects, members of the SIK family regulate a number of metabolic processes, including such cellular processes regulated during AKI as fatty acid metabolism and mitochondrial biogenesis. SIKs are involved in regulating a number of other cellular events which occur during AKI, including apoptosis, the Epithelial to Mesenchymal Transition (EMT), and cell division. Recently, the different SIK kinase isoforms have emerged as promising drug targets, more than 20 new SIK2 inhibitors and activators having been identified by MALDI-TOF screening assays. Their implementation in the future should prove to be important in such renal disease states as AKI. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Lysophosphatidic Acid Signaling in Diabetic Nephropathy
Int. J. Mol. Sci. 2019, 20(11), 2850; https://doi.org/10.3390/ijms20112850 - 11 Jun 2019
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such [...] Read more.
Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such as cell proliferation, migration, and apoptosis. LPA also induces cell damage through complex overlapping pathways, including the generation of reactive oxygen species, inflammatory cytokines, and fibrosis. Several reports indicate that the LPA–LPAR axis plays an important role in various diseases, including kidney disease, lung fibrosis, and cancer. Diabetic nephropathy (DN) is one of the most common diabetic complications and the main risk factor for chronic kidney diseases, which mostly progress to end-stage renal disease. There is also growing evidence indicating that the LPA–LPAR axis also plays an important role in inducing pathological alterations of cell structure and function in the kidneys. In this review, we will discuss key mediators or signaling pathways activated by LPA and summarize recent research findings associated with DN. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Mesenchymal Stem Cells—Potential Applications in Kidney Diseases
Int. J. Mol. Sci. 2019, 20(10), 2462; https://doi.org/10.3390/ijms20102462 - 18 May 2019
Cited by 1
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Glomerular Hematuria: Cause or Consequence of Renal Inflammation?
Int. J. Mol. Sci. 2019, 20(9), 2205; https://doi.org/10.3390/ijms20092205 - 05 May 2019
Abstract
Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal [...] Read more.
Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease. Moreover, gross hematuria, or macrohematuria, promotes acute kidney injury (AKI), with subsequent impairment of renal function in a high proportion of patients. In this pathological context, hemoglobin, heme, or iron released from red blood cells in the urinary space may cause direct tubular cell injury, oxidative stress, pro-inflammatory cytokine production, and further monocyte/macrophage recruitment. The aim of this manuscript is to review the role of glomerular hematuria in kidney injury, the role of inflammation as cause and consequence of glomerular hematuria, and to discuss novel therapies to combat hematuria. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension
Int. J. Mol. Sci. 2019, 20(9), 2138; https://doi.org/10.3390/ijms20092138 - 30 Apr 2019
Abstract
The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such [...] Read more.
The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis
Int. J. Mol. Sci. 2019, 20(8), 1997; https://doi.org/10.3390/ijms20081997 - 23 Apr 2019
Cited by 1
Abstract
Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased [...] Read more.
Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signalling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis
Int. J. Mol. Sci. 2019, 20(8), 1977; https://doi.org/10.3390/ijms20081977 - 23 Apr 2019
Cited by 1
Abstract
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in [...] Read more.
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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Open AccessReview
Potential and Therapeutic Efficacy of Cell-based Therapy Using Mesenchymal Stem Cells for Acute/chronic Kidney Disease
Int. J. Mol. Sci. 2019, 20(7), 1619; https://doi.org/10.3390/ijms20071619 - 01 Apr 2019
Cited by 3
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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