scholarly journals Inhibition of Src Family Kinases Ameliorates LPS-Induced Acute Kidney Injury and Mitochondrial Dysfunction in Mice

2020 ◽  
Vol 21 (21) ◽  
pp. 8246
Author(s):  
Eun Seon Pak ◽  
Md Jamal Uddin ◽  
Hunjoo Ha
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Dysfunction ◽  
Kidney Function ◽  
Mitochondrial Biogenesis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Src Family Kinases ◽  
Src Kinases ◽  
Proximal Tubular

Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis.

MO328ASYMPTOMATIC HYPERURICEMIA ACTS AS ANTIOXIDANT DURING ACUTE KIDNEY INJURY AND DISEASE*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Qiuyue Ma ◽  
Viviane Gnemmi ◽  
Anders Hans-Joachim ◽  
Stefanie Steiger
Keyword(s):  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Epithelial Cells ◽  
Kidney Function ◽  
Metabolic Activity ◽  
Mitochondrial Biogenesis ◽  
Kidney Injury ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Tubular Injury

Abstract Background and Aims Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells. Method Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry. Results We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right). Conclusion Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.

scholarly journals Histopathological Evaluation of Contrast-Induced Acute Kidney Injury Rodent Models

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Norbert Kiss ◽  
Péter Hamar
Keyword(s):  
Acute Kidney Injury ◽  
Animal Studies ◽  
Renal Damage ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Rodent Models ◽  
Histologic Appearance ◽  
Rats And Mice ◽  
To Receive

Contrast-induced acute kidney injury (CI-AKI) can occur in 3–25% of patients receiving radiocontrast material (RCM) despite appropriate preventive measures. Often patients with an atherosclerotic vasculature have to receive large doses of RCM. Thus, animal studies to uncover the exact pathomechanism of CI-AKI are needed. Sensitive and specific histologic end-points are lacking; thus in the present review we summarize the histologic appearance of different rodent models of CI-AKI. Single injection of RCM causes overt renal damage only in rabbits. Rats and mice need an additional insult to the kidney to establish a clinically manifest CI-AKI. In this review we demonstrate that the concentrating ability of the kidney may be responsible for species differences in sensitivity to CI-AKI. The most commonly held theory about the pathomechanism of CI-AKI is tubular cell injury due to medullary hypoxia. Thus, the most common additional insult in rats and mice is some kind of ischemia. The histologic appearance is tubular epithelial cell (TEC) damage; however severe TEC damage is only seen if RCM is combined by additional ischemia. TEC vacuolization is the first sign of CI-AKI, as it is a consequence of RCM pinocytosis and lysosomal fusion; however it is not sensitive as it does not correlate with renal function and is not specific as other forms of TEC damage also cause vacuolization. In conclusion, histopathology alone is insufficient and functional parameters and molecular biomarkers are needed to closely monitor CI-AKI in rodent experiments.

scholarly journals USP10 alleviates sepsis-induced acute kidney injury by regulating Sirt6-mediated Nrf2/ARE signaling pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fei Gao ◽  
Mingjiang Qian ◽  
Guoyue Liu ◽  
Wanping Ao ◽  
Dahua Dai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cell ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Renal Tubular Epithelial Cell ◽  
Renal Tubular

Abstract Background Severe sepsis, a major health problem worldwide, has become one of the leading causes of death in ICU patients. Further study on the pathogenesis and treatment of acute kidney injury (AKI) is of great significance to reduce high mortality rate of sepsis. In this study, the mechanism by which ubiquitin specific peptidase 10 (USP10) reduces sepsis-induced AKI was investigated. Ligation and perforation of cecum (CLP) was employed to establish C57BL/6 mouse models of sepsis. Hematoxylin-eosin (H&E) staining was performed to detect renal injury. The concentrations of serum creatinine (Cr), urea nitrogen (BUN) and cystatin C (Cys C) were determined using a QuantiChrom™ Urea Assay kit. RT-qPCR and western blot were conducted to assess the USP10 expression level. DHE staining was used to detect reactive oxygen species (ROS) levels. H2O2, MDA and SOD levels were assessed using corresponding colorimetric kits. Western blot was used to examine the expression levels of Bcl-2, Bax, cleaved caspase-3, Sirt6, Nrf2 and HO-1. MTT assay was used to determine cell viability, whereas TUNEL staining and flow cytometry were used to assess cell apoptosis. Results In this study, we found that USP10 was decreased in CLP-induced mouse renal tissues. We identified that USP10 alleviated renal dysfunction induced by CLP. Moreover, USP10 was found to reduce oxidative stress, and abated LPS-induced renal tubular epithelial cell injury and apoptosis. Finally, we discovered that USP10 promoted activation of the NRF2/HO-1 pathway through SIRT6 and attenuated LPS-induced renal tubular epithelial cell injury. Conclusions This study found that USP10 activates the NRF2/ARE signaling through SIRT6. USP10 alleviates sepsis-induced renal dysfunction and reduces renal tubular epithelial cell apoptosis and oxidative stress.

scholarly journals Pathophysiology of Cisplatin-Induced Acute Kidney Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Abdullah Ozkok ◽  
Charles L. Edelstein
Keyword(s):  
Acute Kidney Injury ◽  
Proinflammatory Cytokines ◽  
Cell Injury ◽  
Germ Cell Tumors ◽  
Kidney Injury ◽  
Inflammatory Cells ◽  
Chemotherapeutic Agents ◽  
Testicular Germ Cell ◽  
Tubular Necrosis ◽  
Proximal Tubular

Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-αor IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

scholarly journals Kidney-Targeted Redox Scavenger Therapy Prevents Cisplatin-Induced Acute Kidney Injury

2022 ◽  
Vol 12 ◽  
Author(s):  
Ryan M. Williams ◽  
Janki Shah ◽  
Elizabeth Mercer ◽  
Helen S. Tian ◽  
Vanessa Thompson ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Preventive Intervention ◽  
Cell Damage ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Therapeutic Benefit ◽  
Co Morbidity ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. We investigated a drug delivery strategy to improve the pharmacokinetics of an approved therapy that does not normally demonstrate appreciable efficacy in CI-AKI, as a preventive intervention. In prior work, we developed a kidney-selective mesoscale nanoparticle (MNP) that targets the renal proximal tubular epithelium. Here, we found that the nanoparticles target the kidneys in a mouse model of CI-AKI with significant damage. We evaluated MNPs loaded with the reactive oxygen species scavenger edaravone, currently used to treat stroke and ALS. We found a marked and significant therapeutic benefit with edaravone-loaded MNPs, including improved renal function, which we demonstrated was likely due to a decrease in tubular epithelial cell damage and death imparted by the specific delivery of edaravone. The results suggest that renal-selective edaravone delivery holds potential for the prevention of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

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