scholarly journals Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish

2018 ◽  
Author(s):  
Lauren Brilli Skvarca ◽  
Hwa In Han ◽  
Eugenel B. Espiritu ◽  
Maria A. Missinato ◽  
Elizabeth R. Rochon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Cardiac Injury ◽  
Kidney Injury ◽  
Acute Injury ◽  
Cardiomyocyte Proliferation ◽  
Deacetylase Inhibitor ◽  
Summary Statement ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

ABSTRACTAcute kidney injury (AKI) is a serious disorder for which there is no approved pharmaceutical treatment. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 expression, and lowers the number of infiltrating macrophages. Further, we find that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.SUMMARY STATEMENTMortality associated with acute kidney injury (AKI) is in part due to limited treatments available to ameliorate kidney injury. We identified a compound that enhances AKI recovery by promoting cellular dedifferentiation.

scholarly journals Screening of early diagnostic markers of gentamicin-induced acute kidney injury in canines

2019 ◽  
Vol 63 (3) ◽  
pp. 405-411
Author(s):  
Jia-San Zheng ◽  
Jing-Nie ◽  
Ting-Ting Zhu ◽  
Hong-Ri Ruan ◽  
Xue-Wei ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Characteristic Curve ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Fatty Acid Binding ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Transmission Electron ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1 ◽  
Neutrophil Gelatinase

Abstract Introduction The value of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), and liver-type fatty acid binding protein (L-FABP) was assessed in early diagnosis of gentamicin-induced acute kidney injury (AKI) in dogs. Material and Methods Subcutaneous gentamicin injection in 16 healthy adult beagles made the AKI model. Blood was sampled every 6 h to detect NGAL, Kim-1, L-FABP, and serum creatinine (SCr) concentrations. Kidney tissue of two dogs was taken before the injection, as soon as SCr was elevated (78 μmol/L), and when it had risen to 1.5 times the baseline, and haematoxylin-eosin staining and transmission electron microscopy (TEM) were used to observe changes. Results NGAL, Kim-1, and SCr levels were significantly increased (P < 0.05) at 18, 30, and 78 h post injection, but L-FABP concentration was not associated with renal injury. At the earliest SCr elevation stage, findings were mild oedema, degeneration, and vacuolisation in renal tubular epithelial cells in pathology, and mild cytoplasmic and mitochondrial oedema in TEM. At this time point, NGAL and Kim-1 concentrations were significantly increased (P < 0.05), indicating that these two molecules biomark early kidney injury in dogs. Using receiver operating characteristic curve analysis, their warning levels were > 25.31 ng/mL and > 48.52 pg/mL. Conclusion Plasma NGAL and Kim-1 above warning levels are early indicators of gentamicin-induced AKI in dogs.

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 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.

Acute Kidney Injury Induced by Various Pneumoperitoneum Pressures in a Rabbit Model of Mild and Severe Hydronephrosis

2014 ◽  
Vol 94 (2) ◽  
pp. 225-233 ◽  
Author(s):  
Wei Li ◽  
Zhixiu Cao ◽  
Zhongyuan Xia ◽  
Qingtao Meng ◽  
Wei-min Yu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Laparoscopic Surgery ◽  
Serum Creatinine ◽  
Cell Apoptosis ◽  
Rabbit Model ◽  
Kidney Injury ◽  
Acute Injury ◽  
Intraabdominal Pressure ◽  
Pressure Tolerance ◽  
Kidney Injury Molecule 1

Objective: Increased pneumoperitoneum pressure during laparoscopic surgery can result in acute kidney injury. We aimed to clarify whether intraabdominal pressure tolerance is modified in various degrees of unilateral kidney hydronephrosis in rabbits. Methods: A total 90 rabbits were randomly allocated to three groups (group PN, PM and PS, i.e. rabbits with no, mild and severe hydronephrosis, respectively, subjected to intraabdominal pressures). Rabbits in group PM (n = 30) and group PS (n = 30) underwent a surgical procedure inducing a mild or severe left hydronephrosis. Rabbits in all groups were then allocated to 5 subgroups. Then, they were subjected to intraabdominal pressures of 0, 6, 9, 12, and 15 mm Hg, respectively. Acute kidney injury was assessed by measuring serum creatinine (Scr), blood urea nitrogen (BUN), tubular cell apoptosis, kidney injury molecule-1 (KIM-1) and cysteine-rich 61 (Cyr-61/CCN1) expression. Results: Acute kidney injury with increased tubular apoptosis and KIM-1 and Cyr-61 expression occurred when intraabdominal pressure reached 15, 15 and 9 mm Hg in PN, PM and PS groups, respectively. The Scr and BUN levels were similar in all groups. Conclusions: In rabbits, kidneys with severe hydronephrosis were more likely to suffer acute injury when they were exposed to pneumoperitoneal pressure.

scholarly journals Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response

2018 ◽  
Vol 314 (6) ◽  
pp. F1166-F1176 ◽  
Author(s):  
Ritesh K. Srivastava ◽  
Amie M. Traylor ◽  
Changzhao Li ◽  
Wenguang Feng ◽  
Lingling Guo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Chemical Warfare Agent ◽  
Renal Tubules ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Enhanced Production ◽  
Exposed Population ◽  
Renal Tubular ◽  
Kidney Injury Molecule 1

Lewisite (2-chlorovinyldichloroarsine) is an organic arsenical chemical warfare agent that was developed and weaponized during World Wars I/II. Stockpiles of lewisite still exist in many parts of the world and pose potential environmental and human health threat. Exposure to lewisite and similar chemicals causes intense cutaneous inflammatory response. However, morbidity and mortality in the exposed population is not only the result of cutaneous damage but is also a result of systemic injury. Here, we provide data delineating the pathogenesis of acute kidney injury (AKI) following cutaneous exposure to lewisite and its analog phenylarsine oxide (PAO) in a murine model. Both agents caused renal tubular injury, characterized by loss of brush border in proximal tubules and tubular cell apoptosis accompanied by increases in serum creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Interestingly, lewisite exposure enhanced production of reactive oxygen species (ROS) in the kidney and resulted in the activation of autophagic and DNA damage response (DDR) signaling pathways with increased expression of beclin-1, autophagy-related gene 7, and LC-3A/B-II and increased phosphorylation of γ-H2A.X and checkpoint kinase 1/2, respectively. Terminal deoxyribonucleotide-transferase-mediated dUTP nick-end labeling-positive cells were detected in renal tubules along with enhanced proapoptotic BAX/cleaved caspase-3 and reduced antiapoptotic BCL2. Scavenging ROS by cutaneous postexposure application of the antioxidant N-acetyl-l-cysteine reduced lewisite-induced autophagy and DNA damage. In summary, we provide evidence that topical exposure to lewisite causes AKI. The molecular mechanism underlying these changes involves ROS-dependent activation of autophagy and DDR pathway associated with the induction of apoptosis.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 572
Author(s):  
Jung-Yeon Kim ◽  
Jungmin Jo ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Injury ◽  
Manganese Superoxide Dismutase ◽  
Immune Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Pleiotropic Effects ◽  
Induced Apoptosis ◽  
Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

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