scholarly journals Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

2017 ◽  
Vol 41 (2) ◽  
pp. 769-783 ◽  
Author(s):  
Lei Tian ◽  
Xinghua Shao ◽  
Yuanyuan Xie ◽  
Qin Wang ◽  
Xiajing Che ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Macrophage Activation ◽  
Mapk Pathway ◽  
Early Stage ◽  
Kidney Injury ◽  
Mitogen Activated Protein Kinase ◽  
Clinical Samples ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

Background/Aims: Kidney injury molecule-1 (KIM-1) is highly expressed in renal tubular cells after injury and is usually regarded as an early biomarker of acute kidney injury(AKI). The aim of this study was to determine the role of KIM-1 in the development of renal tubular injury Methods: Clinical samples, three different animal models and in vitro experiments were utilized to determine the possible mechanism underlying the involvement of KIM-1 in kidney injury. Results: Both plasma and urinary KIM-1 expression levels were significantly higher in AKI and chronic kidney disease (CKD) patients than in healthy volunteers, and urinary KIM-1 expression was significantly higher in CKD patients than in AKI patients. According to the results of our research involving three different mouse models, KIM-1 expression was significantly increased during the early stage of kidney injury and was persistently elevated in renal fibrosis. Our immunofluorescence staining results indicated that KIM-1-positive tubules were surrounded by macrophage infiltrates in regions of kidney injury. Moreover, our transwell, western blotting and real-time PCR data showed that macrophage migration and phenotype transitions were mediated by KIM-1 through the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway inhibition could significantly reverse the effects of KIM-1 with respect to these macrophage phenotype changes and migration. Conclusions: KIM-1 expression was markedly elevated in both acute and chronic kidney injury and may play a pivotal role in macrophage activation via the MAPK pathway in kidney disease.

scholarly journals The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 20 (20) ◽  
pp. 5238 ◽  
Author(s):  
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Smaranda Radu ◽  
Claudia Florida Costea ◽  
Manuela Ciocoiu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

scholarly journals Diagnostic roles of urinary kidney injury molecule 1 and soluble C5b-9 in acute tubulointerstitial nephritis

2019 ◽  
Vol 317 (3) ◽  
pp. F584-F592 ◽  
Author(s):  
Wen-Ting Zhao ◽  
Jun-Wen Huang ◽  
Ping-Ping Sun ◽  
Tao Su ◽  
Jia-Wei Tang ◽  
...  
Keyword(s):  
Tubulointerstitial Nephritis ◽  
Kidney Injury ◽  
Acute Injury ◽  
Tubular Injury ◽  
Acute Tubulointerstitial Nephritis ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Interstitial Inflammation ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury characterized by inflammatory cells infiltrating in the interstitium. The present study aimed to explore noninvasive biomarkers that might indicate activity of pathological injuries and help direct treatment. Fifty-four patients with clinical-pathologically diagnosed ATIN from January 1, 2014, to June 30, 2016, at Peking University First Hospital were enrolled. Urine samples were collected on the morning of renal biopsy and assessed for urinary kidney injury molecule-1 (KIM-1) and urinary soluble C5b-9 (sC5b-9). Immunofluorescence staining for KIM-1 and C5b-9 was performed in biopsied kidney sections from ATIN cases. The clinical and pathological relevance of the two urinary biomarkers was analyzed. Both urinary KIM-1 and sC5b-9 values were significantly elevated in patients with ATIN compared with healthy controls. The urinary KIM-1 level positively correlated with urinary N-acetyl-β-d-glucosaminidase ( r = 0. 542, P = 0.001) and the pathological tubular injury score ( r = 0.469, P < 0.001), whereas the urinary sC5b-9 level was related to pathological activity scores for tubular injury ( r = 0.413, P = 0.002), interstitial inflammation ( r = 0.388, P = 0.004), and treatment response ( r = 0.564, P < 0.001). Urinary KIM-1 tended to have better diagnostic value for tubular injury than urinary sC5b-9, whereas only urinary sC5b-9 was able to demonstrate severe interstitial inflammation. A combination of urinary KIM-1 and sC5b-9 had an area under the receiver-operating characteristic curve of 0.864 (95% confidence interval: 0.766–0.963, P < 0.001, sensitivity: 75%, specificity: 88%) for acute tissue injury in ATIN. KIM-1 expression was markedly increased in renal tubular cells in both ATIN and acute tubular necrosis conditions, whereas a significant upregulation of C5b-9 was only detected in the tubular cells and interstitial cells in ATIN cases. Urinary KIM-1 is a specific biomarker for renal tubular injury in ATIN, whereas urinary sC5b-9 is valuable in demonstrating severe interstitial inflammation. The combination of these two biomarkers helps identify patients at an acute injury stage and, therefore, might facilitate clinical evaluation and guide immunosuppressive therapy.

scholarly journals Artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pengxun Han ◽  
Yuchun Cai ◽  
Yao Wang ◽  
Wenci Weng ◽  
Yinghui Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Biological Effects ◽  
Kidney Injury ◽  
High Energy ◽  
Redox Imbalance ◽  
Renal Tubular Cells ◽  
Adriamycin Nephropathy ◽  
Renal Tubular ◽  
Tgf Β1

AbstractThe kidney is a high-energy demand organ rich in mitochondria especially renal tubular cells. Emerging evidence suggests that mitochondrial dysfunction, redox imbalance and kidney injury are interconnected. Artemether has biological effects by targeting mitochondria and exhibits potential therapeutic value for kidney disease. However, the underlying molecular mechanisms have not been fully elucidated. This study was performed to determine the effects of artemether on Adriamycin-induced nephropathy and the potential mechanisms were also investigated. In vivo, an Adriamycin nephropathy mouse model was established, and mice were treated with or without artemether for 2 weeks. In vitro, NRK-52E cells were stimulated with TGF-β1 and treated with or without artemether for 24 h. Then renal damage and cell changes were evaluated. The results demonstrated that artemether reduced urinary protein excretion, recovered podocyte alterations, attenuated pathological changes and alleviated renal tubular injury. Artemether also downregulated TGF-β1 mRNA expression levels, inhibited tubular proliferation, restored tubular cell phenotypes and suppressed proliferation-related signalling pathways. In addition, artemether restored renal redox imbalance, increased mtDNA copy number and improved mitochondrial function. In summary, we provided initial evidence that artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice. Artemether may be a promising agent for the treatment kidney disease.

scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

scholarly journals Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 457
Author(s):  
Kyeong-Seok Kim ◽  
Jin-Sol Lee ◽  
Jae-Hyeon Park ◽  
Eun-Young Lee ◽  
Jong-Seok Moon ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Early Stage ◽  
Kidney Injury ◽  
Diabetic Patients ◽  
High Morbidity ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Zucker Diabetic Fatty Rats ◽  
Kidney Injury Molecule 1 ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

scholarly journals Circulating Biomarker Levels in Patients With Stage 5 Chronic Kidney Disease With Respect to Neurovascular Diseases

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 314S-322S
Author(s):  
Justin Lee ◽  
Ryan McMillan ◽  
Leonidas Skiadopoulos ◽  
Vinod Bansal ◽  
José Biller ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Carotid Artery Disease ◽  
Kidney Injury ◽  
Assay Method ◽  
Neurocognitive Deficits ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Intracranial Atherosclerotic Disease ◽  
Artery Disease ◽  
Kidney Injury Molecule 1

The prevalence of neurocognitive deficits remains high in patients with stage 5 chronic kidney disease (CKD5D). Major contributors to such deficits include stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD). The risk of developing these dysfunctional vascular processes is facilitated by the chronic inflammation associated with renal failure. Plasma levels of 10 circulating biomarkers in patients with CKD5D (n = 78-90) were quantified using the sandwich enzyme linked immune sorbent assay method. Biomarkers for this study included kidney injury molecule-1, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), neutrophil gelatinase-associated lipocalin, interleukin-18, endothelin 1, calcifediol, parathyroid hormone, platelet-derived growth factor, microparticles-expressing tissue factor, and lipoprotein(a) (Lp(a)). Of the 90 patients with CKD5D, 30 had CCAD, 24 had ICAD, and 22 had stroke. Lp(a) level was significantly elevated in patients with CKD5D with comorbid ICAD compared to those without (125.70 ± 10.03 ng/mL vs 97.16 ± 5.97 ng/mL; P = .0065). NT-proBNP level was also significantly elevated in patients with CKD5D with comorbid stroke diagnosis compared to those without stroke history, once patients with a diagnosis of heart failure (HF) were excluded (14.84 ± 2.80 ng/mL vs 9.06 ± 1.27 ng/mL; P = .0283). Profiling levels of Lp(a) and NT-ProBNP could thus be useful in the risk stratification of ICAD and stroke, respectively, in the CKD5D population.

Urinary TCP1-eta: A Cortical Damage Marker for the Pathophysiological Diagnosis and Prognosis of Acute Kidney Injury

2019 ◽  
Vol 174 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Sandra M Sancho-Martínez ◽  
Fernando Sánchez-Juanes ◽  
Víctor Blanco-Gozalo ◽  
Miguel Fontecha-Barriuso ◽  
Laura Prieto-García ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Cortical Damage ◽  
Renal Tubular Cells ◽  
Tubular Necrosis ◽  
Diagnosis And Prognosis ◽  
A Cell ◽  
Renal Tubular ◽  
Dextran Solution

Abstract Acute kidney injury (AKI) is a serious syndrome with increasing incidence and health consequences, and high mortality rate among critically ill patients. Acute kidney injury lacks a unified definition, has ambiguous semantic boundaries, and relies on defective diagnosis. This, in part, is due to the absence of biomarkers substratifying AKI patients into pathophysiological categories based on which prognosis can be assigned and clinical treatment differentiated. For instance, AKI involving acute tubular necrosis (ATN) is expected to have a worse prognosis than prerenal, purely hemodynamic AKI. However, no biomarker has been unambiguously associated with tubular cell death or is able to provide etiological distinction. We used a cell-based system to identify TCP1-eta in the culture medium as a noninvasive marker of damaged renal tubular cells. In rat models of AKI, TCP1-eta was increased in the urine co-relating with renal cortical tubule damage. When kidneys from ATN rats were perfused in situ with Krebs-dextran solution, a portion of the urinary TCP1-eta protein content excreted into urine disappeared, and another portion remained within the urine. These results indicated that TCP1-eta was secreted by tubule cells and was not fully reabsorbed by the damaged tubules, both effects contributing to the increased urinary excretion. Urinary TCP1-eta is found in many etiologically heterogeneous AKI patients, and is statistically higher in patients partially recovered from severe AKI. In conclusion, urinary TCP1-eta poses a potential, substratifying biomarker of renal cortical damage associated with bad prognosis.

scholarly journals Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1934-1942 ◽  
Author(s):  
Aparna Krishnamoorthy ◽  
Amrendra Kumar Ajay ◽  
Dana Hoffmann ◽  
Tae-Min Kim ◽  
Victoria Ramirez ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
High Sensitivity ◽  
Kidney Damage ◽  
Therapeutic Interventions ◽  
Mrna Levels ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Injury And Repair

AbstractIschemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

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