scholarly journals Tetramethylpyrazine Prevents Contrast-Induced Nephropathy via Modulating Tubular Cell Mitophagy and Suppressing Mitochondrial Fragmentation, CCL2/CCR2-Mediated Inflammation, and Intestinal Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xuezhong Gong ◽  
Yiru Duan ◽  
Junli Zheng ◽  
Zi Ye ◽  
Tom K. Hei
Keyword(s):  
Western Blot ◽  
Kidney Injury ◽  
Intestinal Injury ◽  
Renal Tubules ◽  
Mitochondrial Fragmentation ◽  
Contrast Induced Nephropathy ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Small Intestinal Injury ◽  
Small Intestinal

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI), but detailed pathogenesis and effectual remedy remain elusive. Here, we tested the hypothesis that contrast media (CM) impaired mitochondrial quality control (MQC) in tubules, including mitochondrial fragmentation and mitophagy, induced systemic inflammation, and intestinal injury. Since we previously demonstrated that the natural antioxidant 2,3,5,6-tetramethylpyrazine (TMP) can be a protectant against CIN, we moreover investigated the involved renoprotective mechanisms of TMP. In a well-established CIN rat model, renal functions, urinary AKI biomarkers, and renal reactive oxygen species (ROS) production were measured. Mitochondrial damage and mitophagy were detected by transmission electron microscopy (TEM) and western blot. The abundance of Drp1 and Mfn2 by western blot and immunohistochemistry (IHC) was used to evaluate mitochondrial fragmentation. TUNEL staining, TEM, and the abundance of cleaved-caspase 3 and procaspase 9 were used to assay apoptosis. We demonstrated that increased mitophagy, mitochondrial fragmentation, ROS generation, autophagy, and apoptosis occurred in renal tubular cells. These phenomena were accompanied by renal dysfunction and an increased excretion of urinary AKI biomarkers. Meanwhile, CM exposure resulted in concurrent small intestinal injury and villous capillary endothelial apoptosis. The abundance of the inflammatory cytokines CCL2 and CCR2 markedly increased in the renal tubules of CIN rats, accompanied by increased concentrations of IL-6 and TNF-α in the kidneys and the serum. Interestingly, TMP efficiently prevented CM-induced kidney injury in vivo by reversing these pathological processes. Mechanistically, TMP inhibited the CM-induced activation of the CCL2/CCR2 pathway, ameliorated renal oxidative stress and aberrant mitochondrial dynamics, and modulated mitophagy in tubular cells. In summary, this study demonstrated novel pathological mechanisms of CIN, that is, impairing MQC, inducing CCL2/CCR2-mediated inflammation and small intestinal injury, and provided novel renoprotective mechanisms of TMP; thus, TMP may be a promising therapeutic agent for CIN.

scholarly journals miR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury

2021 ◽  
pp. 1-11
Author(s):  
Yue Zhao ◽  
Yue Lang ◽  
Mingchao Zhang ◽  
Shaoshan Liang ◽  
Xiaodong Zhu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Kidney Injury ◽  
Immunofluorescent Staining ◽  
Luciferase Reporter ◽  
Mitochondrial Fragmentation ◽  
Tubular Cells ◽  
Renal Tubular Cells

<b><i>Background:</i></b> Mitochondria are dynamic organelles whose structure are maintained by continuous fusion and fission. During acute kidney injury (AKI) progression, mitochondrial fission in renal tubular cells was elevated, characterized by mitochondrial fragmentation. It is tightly associated with mitochondrial dysfunction, which has been proven as a critical mechanism responsible for AKI. However, the initiating factor for the disruption of mitochondrial dynamics in AKI was not well understood. <b><i>Objectives:</i></b> To explore the molecular mechanisms of mitochondrial disorders and kidney damage. <b><i>Methods:</i></b> We established cisplatin-induced AKI model in C57BL/6 mice and proximal tubular cells, and detected the expression of miR-125b by qPCR. Then we delivered miR-125b antagomir after cisplatin treatment in mice via hydrodynamic-based gene transfer technique. Subsequently, we performed luciferase reporter and immunoblotting ­assays to prove miR-125b could directly modulate mitofusin1 (MFN1) expression. We also tested the role of miR-125b in mitochondrial and renal injury through immunofluorescent staining, qPCR, and immunoblotting assays. <b><i>Results:</i></b> miR-125b levels were induced in cisplatin-challenged mice and cultured tubular cells. Anti-miR-125b could effectively alleviate cisplatin-induced mitochondrial fragmentation and kidney injury both in vitro and in vivo. Furthermore, miR-125b could directly regulate MFN1, which is a key regulator of mitochondrial fusion. Our study indicated that miR-125b is upregulated during cisplatin-induced AKI. Inhibition of miR-125b may suppress mitochondrial and renal damage through upregulating MFN1. This study suggests that miR-125b could be a potential therapeutic target in AKI.

scholarly journals Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

2017 ◽  
Vol 312 (3) ◽  
pp. F502-F515 ◽  
Author(s):  
Yingfeng Shi ◽  
Liuqing Xu ◽  
Jinhua Tang ◽  
Lu Fang ◽  
Shuchen Ma ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Kidney Injury ◽  
Acute Injury ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.

scholarly journals SARS-CoV-2 Causes Acute Kidney Injury by Directly Infecting Renal Tubules

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhaohui Chen ◽  
Junyi Hu ◽  
Lilong Liu ◽  
Rong Chen ◽  
Miao Wang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cohort Analysis ◽  
Kidney Injury ◽  
Human Kidney ◽  
Cell Types ◽  
Progressive Increase ◽  
Renal Tubules ◽  
Spike Gene ◽  
Tubular Cells ◽  
Renal Tubular Cells

Acute kidney injury (AKI) is one of the most prevalent complications among hospitalized coronavirus disease 2019 (COVID-19) patients. Here, we aim to investigate the causes, risk factors, and outcomes of AKI in COVID-19 patients. We found that angiotensin-converting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) were mainly expressed by different cell types in the human kidney. However, in autopsy kidney samples, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein was detected in ACE2+ or TMPRSS2+ renal tubular cells, whereas the RNAscope® Assay targeting the SARS-CoV-2 Spike gene was positive mainly in the distal tubular cells and seldom in the proximal tubular cells. In addition, the TMPRSS2 and kidney injury marker protein levels were significantly higher in the SARS-CoV-2-infected renal distal tubular cells, indicating that SARS-CoV-2-mediated AKI mainly occurred in the renal distal tubular cells. Subsequently, a cohort analysis of 722 patients with COVID-19 demonstrated that AKI was significantly related to more serious disease stages and poor prognosis of COVID-19 patients. The progressive increase of blood urea nitrogen (BUN) level during the course of COVID-19 suggests that the patient’s condition is aggravated. These results will greatly increase the current understanding of SARS-CoV-2 infection.

scholarly journals Prevention of Traditional NSAID-Induced Small Intestinal Injury: Recent Preliminary Studies Using Capsule Endoscopy

Digestion ◽  
2010 ◽  
Vol 82 (3) ◽  
pp. 167-172 ◽  
Author(s):  
Shunji Fujimori ◽  
Yoko Takahashi ◽  
Tsuguhiko Seo ◽  
Katya Gudis ◽  
Akihito Ehara ◽  
...  
Keyword(s):  
Capsule Endoscopy ◽  
Intestinal Injury ◽  
Traditional Nsaid ◽  
Small Intestinal Injury ◽  
Small Intestinal

SMALL INTESTINAL INJURY ASSOCIATED WITH PELVIC FRACTURES

1983 ◽  
Vol 23 (7) ◽  
pp. 652
Author(s):  
Peter Mucha ◽  
Michael B. Farnell ◽  
Richard S. Bryan
Keyword(s):  
Pelvic Fractures ◽  
Intestinal Injury ◽  
Small Intestinal Injury ◽  
Small Intestinal

Abstract 188: Loss of Renal Prolyl Carboxypeptidase in Mice With Chronic Kidney Disease

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Orly Leiva ◽  
Khalid M Elased ◽  
Mariana Morris ◽  
Nadja Grobe
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Western Blot ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Left Renal Artery ◽  
Renal Tubules ◽  
Ang Ii ◽  
Chronic Kidney Injury

There are 26 million adults with chronic kidney disease (CKD) in the U.S. and the incidence continues to increase. It is well documented that the activation of the renin angiotensin system and the elevated formation of angiotensin (Ang) II both contribute to renal pathophysiology in CKD. Emerging evidence suggests that the Ang II degrading protease prolyl carboxypeptidase (PCP) is renoprotective. Thus, we investigated protein expression and activity of renal PCP using immunofluorescence, western blot and mass spectrometry in a mouse model of CKD. Renal injury in male C57Bl6 mice was caused by constriction of the left renal artery using silver clips (2K1C-method). Blood pressure measurements by radiotelemetry revealed a significant increase of 36.1 ± 3.9 mm Hg in 2K1C animals compared with control animals 1 week after clip placement (p<0.0001). Using immunofluorescence and confocal microscopy, PCP was localized in the Bowman’s capsule of the glomerulus and in proximal and distal renal tubules. Western blot analysis showed PCP was significantly reduced in clipped 2K1C kidneys compared to unclipped kidneys of the 2K1C mice or compared to control mice (clipped 0.04 ± 0.02 vs unclipped 0.58 ± 0.16 vs control 0.65 ± 0.18, p < 0.05). In addition, renal PCP enzyme activity was found to be markedly reduced in 2K1C kidneys as assessed by mass spectrometric based enzyme assays (clipped 37.1 ± 4.3 pmol Ang-(1-7)/h/μg vs unclipped 77.3 ± 12.3 pmol Ang-(1-7)/h/μg vs control 120.7 ± 14.7 pmol Ang-(1-7)/h/μg, p < 0.01). In contrast, protein expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected. Notably, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion (clipped 34.6 ± 3.1 vs unclipped 52.1 ± 4.0 vs control 1.2 ± 2.1, p < 0.0001) and renal fibrosis (clipped 57.5 ± 0.9 vs unclipped 33.0 ± 0.7 vs control 3.3 ± 0.2, p < 0.0001). Results suggest that PCP is suppressed in chronic kidney injury and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PCP. Therefore, Ang II processing by PCP may have clinical implications in patients with renal pathologies.

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