scholarly journals An Immunohistochemical Investigation of Renal Phospholipidosis and Toxicity in Rats

2017 ◽  
Vol 36 (5) ◽  
pp. 386-394 ◽  
Author(s):  
Jing Ying Ma ◽  
Sandra Snook ◽  
Sheryl Garrovillo ◽  
Charles Johnson ◽  
David La
Keyword(s):  
Electron Microscopy ◽  
Membrane Protein ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Vehicle Group ◽  
Tubular Injury ◽  
Histamine H4 Receptor ◽  
Outer Stripe ◽  
H4 Receptor ◽  
Renal Tubular

Immunohistochemical staining for the lysosome-associated membrane protein 2 (LAMP-2) has been proposed previously as an alternative to electron microscopy to identify hepatic phospholipidosis. This study used LAMP-2 immunohistochemistry (IHC) to diagnose phospholipidosis in rats exhibiting renal tubular injury. Rats were administered toreforant, a histamine H4 receptor antagonist by oral gavage at a dose of 3, 10, or 100 mg/kg/d for 6 months. Hematoxylin and eosin staining revealed renal tubular epithelial cell vacuolation, hypertrophy, degeneration, and luminal dilation in the 100 mg/kg/d group animals. Renal tubular injury was confirmed using kidney injury marker 1 (KIM-1) IHC. The involvement of phosopholipidosis in the renal injury was investigated by LAMP-2. Adipophilin IHC was included to differentiate phospholipidosis from lipidosis. Increased LAMP-2 staining was observed in the 100 mg/kg/d group animals when compared to vehicle group animals. Lysosome-associated membrane protein-2 staining was most prominent in the outer stripe of the outer medulla where KIM-1 staining was also most prominent. By contrast, adipophilin staining was not increased. Phospholipidosis was also confirmed by electron microscopy. These data support the use of LAMP-2 IHC as a diagnostic tool and suggest an association between phospholipidosis and the renal tubular injury caused by toreforant.

scholarly journals Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 152
Author(s):  
Chia-Chu Liu ◽  
Chia-Fang Wu ◽  
Yung-Chin Lee ◽  
Tsung-Yi Huang ◽  
Shih-Ting Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Manganese Superoxide Dismutase ◽  
Kidney Injury ◽  
Normal Function ◽  
Nucleotide Polymorphisms ◽  
Tubular Injury ◽  
Single Nucleotide ◽  
Manganese Superoxide ◽  
Calcium Urolithiasis ◽  
Renal Tubular

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

scholarly journals CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Antoine Dewitte ◽  
Julien Villeneuve ◽  
Sébastien Lepreux ◽  
Marion Bouchecareilh ◽  
Xavier Gauthereau ◽  
...  
Keyword(s):  
Blood Platelets ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Hypoxic Stress ◽  
Tubular Epithelium ◽  
Tubular Epithelial Cells ◽  
Tubular Injury ◽  
Short Term ◽  
Inflammatory Agent ◽  
Hypoxic Conditions

Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.

scholarly journals Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model

2019 ◽  
Vol 317 (2) ◽  
pp. F264-F274 ◽  
Author(s):  
Satoshi Tanimura ◽  
Katsuyuki Tanabe ◽  
Hiromasa Miyake ◽  
Kana Masuda ◽  
Keigo Tsushida ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endothelial Cells ◽  
Kidney Injury ◽  
Protective Effects ◽  
Tubular Injury ◽  
Injury Model ◽  
Peritubular Capillaries ◽  
Renal Tubular ◽  
And Function ◽  
Hospital Acquired

Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/−) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/− mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/− mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries.

scholarly journals Inhibition of Mitochondrial Complex I Aggravates Folic Acid-Induced Acute Kidney Injury

2019 ◽  
Vol 44 (5) ◽  
pp. 1002-1013 ◽  
Author(s):  
Wen Zhang ◽  
Yunwen Yang ◽  
Huiping Gao ◽  
Yue Zhang ◽  
Zhanjun Jia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Folic Acid ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Kidney Injury ◽  
Mitochondrial Complex I ◽  
Tubular Injury ◽  
Mitochondrial Complex ◽  
Renal Tubular

Background: Some researches revealed that mitochondrial dysfunction is associated with various kidney injury. However, the role of mitochondrial dysfunction in the pathogenesis of acute kidney injury (AKI) still needs evidence. Methods: We evaluated the effect of mitochondrial complex I inhibitor rotenone on folic acid (FA)-induced AKI in mice. Results: Strikingly, the mice pretreated with rotenone at a dose of 200 ppm in food showed exacerbated kidney injury as shown by higher levels of blood urea nitrogen and creatinine compared with FA alone group. Meanwhile, both renal tubular injury score and the expression of renal tubular injury marker neutrophil gelatinase-associated lipocalin were further elevated in rotenone-pretreated mice, suggesting the deteriorated renal tubular injury. Moreover, the decrements of mitochondrial DNA copy number and the expressions of mitochondrial Cytochrome c oxidase subunit 1, mitochondrial NADH dehydrogenase subunit 1, and mitochondria-specific superoxide dismutase (SOD2) in the kidneys of FA-treated mice were further reduced in rotenone-pretreated mice, indicating the aggravated mitochondrial damage. In parallel with the SOD2 reduction, the oxidative stress markers of malondialdehyde and HO-1 displayed greater increment in AKI mice with rotenone pretreatment in line with the deteriorated apoptotic response and inflammation. Conclusion: Our results suggested that the inhibition of mitochondrial complex I activity aggravated renal tubular injury, mitochondrial damage, oxidative stress, cell apoptosis, and inflammation in FA-induced AKI.

scholarly journals Lack of significant renal tubular injury despite acute kidney injury in acute decompensated heart failure

2012 ◽  
Vol 14 (6) ◽  
pp. 597-604 ◽  
Author(s):  
Matthias Dupont ◽  
Kevin Shrestha ◽  
Dhssraj Singh ◽  
Adiveh Awad ◽  
Cynthia Kovach ◽  
...  
Keyword(s):  
Heart Failure ◽  
Acute Kidney Injury ◽  
Acute Decompensated Heart Failure ◽  
Kidney Injury ◽  
Decompensated Heart Failure ◽  
Tubular Injury ◽  
Renal Tubular

scholarly journals Cholemic Nephropathy Reloaded

2019 ◽  
Vol 40 (01) ◽  
pp. 091-100 ◽  
Author(s):  
Peter Fickert ◽  
Alexander R. Rosenkranz
Keyword(s):  
Cell Injury ◽  
Current Knowledge ◽  
Morphological Characteristics ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Research Strategy ◽  
Tubular Injury ◽  
Histomorphological Changes ◽  
Key Questions ◽  
Pathophysiologic Mechanisms

AbstractAcute kidney injury (AKI) is a dreaded complication in patients with liver disease and jaundice, since it is associated with significant morbidity and mortality. Cholemic nephropathy (CN) is thought to represent a widely underestimated important cause of AKI in advanced liver diseases with jaundice. The umbrella term CN describes impaired renal function along with histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed primarily toward distal nephron segments. In cholestasis, biliary constituents may be excreted via the kidney and bilirubin or bile acids may trigger tubular injury and cast formation, but as we begin to understand the underlying pathophysiologic mechanisms, we become increasingly aware of the urgent need for clearly defined diagnostic criteria. In the following, we aim to summarize current knowledge of clinical and morphological characteristics of CN, discuss potential pathomechanisms, and raise key questions to stimulate evolution of a research strategy for CN.

scholarly journals Glycogen Synthase Kinase-3 Signaling in Acute Kidney Injury

Nephron ◽  
2020 ◽  
Vol 144 (12) ◽  
pp. 609-612
Author(s):  
Abeda Jamadar ◽  
Reena Rao
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Clinical Syndrome ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Renal Tubular

Acute kidney injury (AKI) is a common clinical syndrome that involves renal tubular epithelial cell death and leads to acute decline in renal function. Improper tubular regeneration following AKI often leads to CKD. We discuss the role of a serine/threonine protein kinase called glycogen synthase kinase-3 (GSK3) in renal tubular injury and renal fibrosis. We also highlight the importance of GSK3 as a potential drug target in AKI patients and molecular mechanisms promoting tissue regeneration.

Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E

2020 ◽  
Vol 318 (3) ◽  
pp. F793-F803 ◽  
Author(s):  
Lele Liu ◽  
Yuanjun Deng ◽  
Yang Cai ◽  
Pingfan Lu ◽  
Yiyan Guo ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Renal Tubule ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Cell Regeneration ◽  
Cyclin Dependent Kinase ◽  
Renal Tubular Epithelial Cell ◽  
Cyclin E1 ◽  
Renal Tubular

Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKO mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.

The Utility of Novel Urinary Biomarkers in Mice for Drug Development Studies

2020 ◽  
pp. 109158182097049
Author(s):  
Adeyemi O. Adedeji ◽  
Yi-Zhong Gu ◽  
Tony Pourmohamad ◽  
Justin Kanerva ◽  
Yafei Chen ◽  
...  
Keyword(s):  
Early Detection ◽  
Drug Development ◽  
Mouse Strain ◽  
Kidney Injury ◽  
Urinary Biomarkers ◽  
Development Studies ◽  
Tubular Injury ◽  
Biomarker Response ◽  
Highly Sensitive ◽  
Renal Tubular

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.

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