Dexmedetomidine Protects against Ischemia and Reperfusion-Induced Kidney Injury in Rats

Acute kidney injury (AKI), a clinical syndrome, is a sudden onset of kidney failure that severely affects the kidney tubules. One potential treatment is dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist that is used as an anesthetic adjuvant. It also has anti-inflammatory, neuroprotective, and sympatholytic qualities. The aim of this study was to establish whether DEX also offers protection against ischemia and reperfusion- (I/R-) induced AKI in rats. An intraperitoneal injection of DEX (25 μg/kg) was administered 30 min prior to the induction of I/R. The results indicate that in the I/R rats, DEX played a protective role by reducing the damage to the tubules and maintaining renal function. Furthermore, in response to I/R, the DEX treatment reduced the mRNA expression of TNF-α, IL-1β, IL-6, and MCP-1 in the kidney tissues and the serum levels of TNF-α, IL-1β, IL-6, and MCP-1. DEX also reduced the levels of oxidative stress and apoptosis in the tubular cells. These results indicate that in response to I/R kidney injury, DEX plays a protective role by inhibiting inflammation and tubular cell apoptosis, reducing the production of reactive oxygen species, and promoting renal function.

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CO-Releasing Molecule-2 Prevents Acute Kidney Injury through Suppression of ROS-Fyn-ER Stress Signaling in Mouse Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9947772 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Md Jamal Uddin ◽

Jeewon Jeong ◽

Eun Seon Pak ◽

Hunjoo Ha

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Er Stress ◽

Stress Responses ◽

Kidney Diseases ◽

Kidney Injury ◽

Oxygen Species ◽

Chronic Kidney Diseases ◽

Tubular Cells ◽

Cellular Apoptosis

Acute kidney injury (AKI) most commonly appears in critically ill patients in hospitals. AKI is characterized as a quick deterioration of kidney function and has recently been identified to be tightly interlinked with chronic kidney diseases. The emerging major mediators of AKI include oxidative stress and endoplasmic reticulum (ER) stress. Carbon monoxide (CO) attenuates oxidative stress and ER stress in various cells, while Fyn, a member of the Src kinase family, is activated by oxidative stress and contributes to ER stress in skeletal muscle. Considering these, the objective of the current research was to determine (i) the involvement of Fyn in ER stress-mediated AKI and (ii) the effect of CO-releasing molecule-2 (CORM2) on reactive oxygen species- (ROS-) Fyn-ER stress-mediated AKI. Pretreatment with CORM2 (30 mg/kg) efficiently inhibited LPS (30 mg/kg)-induced oxidative stress, inflammation, and cellular apoptosis during AKI in C57BL/6J mice. Also, CORM2 efficiently suppressed the activation of Fyn and ER stress in AKI mice. Consistently, pretreatment with CORM2 inhibited oxidative stress, Fyn activation, ER stress, inflammation, and apoptosis in LPS- or H2O2-stimulated proximal epithelial tubular cells. Fyn inhibition using siRNA or an inhibitor (PP2) significantly attenuated ER stress responses in the cells. These data suggest that CORM2 may become a potential treatment option against ROS-Fyn-ER stress-mediated AKI.

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Diagnosis of oliguria and acute kidney injury

10.1093/med/9780199600830.003.0212 ◽

2016 ◽

Author(s):

John A. Kellum

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Extracellular Volume ◽

Kidney Injury ◽

Clinical Problem ◽

Clinical Syndrome ◽

Volume Depletion ◽

International Consensus ◽

Tubular Necrosis ◽

Diagnosis And Classification

Diagnosis and classification of acute pathology in the kidney is major clinical problem. Azotemia and oliguria represent not only disease, but also normal responses of the kidney to extracellular volume depletion or a decreased renal blood flow. Clinicians routinely make inferences about both the presence of renal dysfunction and its cause. Pure prerenal physiology is unusual in hospitalized patients and its effects are not necessary benign. Sepsismay alter renal function without the characteristic changes in urine indices. The clinical syndrome known as acute tubular necrosis does not actually manifest the histological changes that the name implies. Acute kidney injury (AKI) is a term proposed to encompass the entire spectrum of the syndrome from minor changes in renal function to a requirement for renal replacement therapy. Criteria based on both changes in serum creatinine and urine output represent a broad international consensus for diagnosing and staging AKI.

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Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6286984 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 3

Author(s):

Xue Li ◽

Yu Zou ◽

Jia Xing ◽

Yuan-Yuan Fu ◽

Kai-Yue Wang ◽

...

Keyword(s):

Renal Function ◽

Folic Acid ◽

Nuclear Translocation ◽

Early Stage ◽

Kidney Injury ◽

Protective Role ◽

Iron Accumulation ◽

Inflammatory Factors ◽

Nrf2 Activation

Folic acid- (FA-) induced kidney injury is characterized by the tubule damage due to the disturbance of the antioxidant system and subsequent interstitial fibrosis. FG-4592 is an inhibitor of prolyl hydroxylase of hypoxia-inducible factor (HIF), an antioxidant factor. The present study investigated the protective role of FG-4592 pretreatment at the early stage of the kidney injury and long-term impact on the progression of renal fibrosis. FG-4592 was administrated two days before FA injection in mice. On the second day after FA injection, the mice with FG-4592 pretreatment showed an improved renal function, compared with those without FG-4592 pretreatment, indicated by biochemical and histological parameters; meanwhile, the cellular content of iron, malondialdehyde, and 4-hydroxynonenal histologically decreased, implying the suppression of iron accumulation and lipid peroxidation. Simultaneously, upregulation of HIF-1α was found, along with Nrf2 activation, which was reflected by increased nuclear translocation and high-expression of downstream proteins, including heme-oxygenase1, glutathione peroxidase4, and cystine/glutamate transporter, as well as ferroportin. Correspondingly, the elevated levels of antioxidative enzymes and glutathione, as well as reduced iron accumulation, were observed, suggesting a lower risk of occurrence of ferroptosis with FG-4592 pretreatment. This was confirmed by reversed pathological parameters and improved renal function in FA-treated mice with the administration of ferrostatin-1, a specific ferroptosis inhibitor. Furthermore, a signal pathway study indicated that Nrf2 activation was associated with increased phosphorylation of Akt and GSK-3β, verified by the use of an inhibitor of the PI3K that phosphorylates Akt. Moreover, FG-4592 pretreatment also decreased macrophage infiltration and expression of inflammatory factors TNF-α and IL-1β. On the 14th day after FA injection, FG-4592 pretreatment decreased collagen deposition and expression of fibrosis biomarkers. These findings suggest that the protective role of FG-4592 pretreatment is achieved mainly by decreasing ferroptosis at the early stage of FA-induced kidney injury via Akt/GSK-3β-mediated Nrf2 activation, which retards the fibrosis progression.

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Platelet-rich Plasma Enhanced MSCs Repair for Glycerin-induced Acute Kidney Injury via AKT/Rab27 Paracrine Pathway

10.21203/rs.3.rs-33696/v1 ◽

2020 ◽

Author(s):

Cheng Ji ◽

Jiahui Zhang ◽

Hui Shi ◽

wanzhu Liu ◽

Fengtian Sun ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Renal Function ◽

Platelet Rich Plasma ◽

Kidney Injury ◽

Human Umbilical Cord ◽

Tubular Cells ◽

Renal Tubular Cells

Abstract Background: Acute kidney injury (AKI) was defined by rapid deterioration of renal function, as a common complication in hospitalized patients. Among the recent therapeutic options, mesenchymal stem cells (MSCs) were considered a promising strategy for damaged tissues repair. Platelet rich plasma (PRP) regulates stromal cells to repair tissue damage through the release of growth factors. Here we proposed a possible therapeutic use of human umbilical cord mesenchymal stem cells stimulated by platelet-rich plasma (PRP-MSCs) in a murine model of acute renal injury generated by glycerin injection.Methods: In vivo, we constructed cisplatin-induced acute kidney injury rat models. On day 1 post injury, rat received a tail vein injection of 1×106 MSCs and 1×106 PRP-MSCs. All animals were sacrificed at Day 3 after glycerin injection. Renal function (serum BUN, Creatinine), histopathological structure changes and tubular cells apoptosis were evaluated. In vitro experiment, 50 μmol/L of glycerin treated NRK-52E for 12h were incubated with MSC or PRP-MSC for 24h in transwell co-culture system. Cells were harvested for apoptosis assay, immunofluorescence assay, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR).Results: In vivo and vitro studies confirmed that the PRP induced YAP nucleus expression to promoting the proliferation and reinforces the stemness of MSCs, and stimulated the paracrine exosomes of MSCs by activating AKT/Rab27 signaling pathway to inhibiting the apoptosis of renal tubular cells. Conclusions: Our results revealed a novel potential use of PRP-MSCs as therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor PRP-MSCs.

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CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00178.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. F1064-F1073 ◽

Cited By ~ 49

Author(s):

Nanmei Liu ◽

Andreas Patzak ◽

Jinyuan Zhang

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Kidney Injury ◽

Cell Death ◽

Mesenchymal Stem Cells ◽

Renal Function ◽

Caspase 3 ◽

Kidney Injury ◽

Nuclear Antigen ◽

Tubular Cells

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves the repair ability of BMSCs and that this is related to increased homing of BMSCs and increased release of cytokines. Hypoxia/reoxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs, and CXCR4-BMSCs were cocultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death, and expressions of cleaved caspase-3 and Bcl-2 in cocultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions of the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation, and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18+ cells in BMSCs, null-BMSCs, and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of bone morphogenetic protein-7, hepatocyte growth factor, and interleukin 10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In cocultured HR-RTECs the proportions of PCNA+ cells and Bcl-2 expression were enhanced; however, the proportion of annexin V+ cells and expression of cleaved caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, which was associated with improved renal function, reduced acute tubular necrosis scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy for AKI.

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zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function

AJP Renal Physiology ◽

10.1152/ajprenal.00659.2011 ◽

2012 ◽

Vol 303 (8) ◽

pp. F1239-F1250 ◽

Cited By ~ 46

Author(s):

Christian Herzog ◽

Cheng Yang ◽

Alexandrea Holmes ◽

Gur P. Kaushal

Keyword(s):

Renal Function ◽

Therapeutic Agent ◽

Kidney Injury ◽

Protective Role ◽

Autophagic Flux ◽

Tubular Epithelial Cells ◽

Cisplatin Nephrotoxicity ◽

Autophagy Pathway ◽

Renal Tubular

Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.

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Blockade of sodium-glucose cotransporter 2 suppresses high glucose-induced angiotensinogen augmentation in renal proximal tubular cells

AJP Renal Physiology ◽

10.1152/ajprenal.00402.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. F67-F75 ◽

Cited By ~ 2

Author(s):

Ryousuke Satou ◽

Michael W. Cypress ◽

T. Cooper Woods ◽

Akemi Katsurada ◽

Courtney M. Dugas ◽

...

Keyword(s):

Diabetes Mellitus ◽

Angiotensin Ii ◽

Kidney Injury ◽

Intracellular Reactive Oxygen Species ◽

Oxygen Species ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Sodium Glucose Cotransporter ◽

Proximal Tubular ◽

Renal Proximal Tubular

Renal proximal tubular angiotensinogen (AGT) is increased by hyperglycemia (HG) in diabetes mellitus, which augments intrarenal angiotensin II formation, contributing to the development of hypertension and kidney injury. Sodium-glucose cotransporter 2 (SGLT2) is abundantly expressed in proximal tubular cells (PTCs). The present study investigated the effects of canagliflozin (CANA), a SGLT2 inhibitor, on HG-induced AGT elevation in cultured PTCs. Mouse PTCs were treated with 5–25 mM glucose. CANA (0–10 µM) was applied 1 h before glucose treatment. Glucose (10 mM) increased AGT mRNA and protein levels at 12 h (3.06 ± 0.48-fold in protein), and 1 and 10 µM CANA as well as SGLT2 shRNA attenuated the AGT augmentation. CANA did not suppress the elevated AGT levels induced by 25 mM glucose. Increased AGT expression induced by treatment with pyruvate, a glucose metabolite that does not require SGLT2 for uptake, was not attenuated by CANA. In HG-treated PTCs, intracellular reactive oxygen species levels were elevated compared with baseline (4.24 ± 0.23-fold), and these were also inhibited by CANA. Furthermore, tempol, an antioxidant, attenuated AGT upregulation in HG-treated PTCs. HG-induced AGT upregulation was not inhibited by an angiotensin II receptor antagonist, indicating that HG stimulates AGT expression in an angiotensin II-independent manner. These results indicate that enhanced glucose entry via SGLT2 into PTCs elevates intracellular reactive oxygen species generation by stimulation of glycolysis and consequent AGT augmentation. SGLT2 blockade limits HG-induced AGT stimulation, thus reducing the development of kidney injury in diabetes mellitus.

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The Effect of Estradiol on Renal Function in Reversible and Irreversible Unilateral Ureteral Obstruction in Rats

The Indonesian Biomedical Journal ◽

10.18585/inabj.v10i3.459 ◽

2018 ◽

Vol 10 (3) ◽

pp. 263-9

Author(s):

Zahra Lak ◽

Akbar Vahdati ◽

Mehdi Nematbakhsh

Keyword(s):

Renal Function ◽

Ureteral Obstruction ◽

Serum Levels ◽

Protective Role ◽

Estradiol Treatment ◽

Group 13 ◽

Reduced Body ◽

Group 5 ◽

Group 2

BACKGROUND: The ureteral obstruction (UO) is the most common clinical disorders. This study was designed to investigate the renoprotective effect of estradiol in unilateral UO (UUO) and reversible UUO (RUUO).METHODS: Eighty-four ovareictomized Wistar rats were assigned into 14 groups. Group 1 was sham operated group. All the groups 2-14 were subject to UUO, however they received additional treatments. Group 2-4 received test substances (vehicle, 0.1 or 0.05 mg/kg of estradiol) and sacrificed after 3 days. Group 5-7 received test substances and after 3 days followed by RUUO (obstruction removal) and after one day post RUUO were sacrificed. Group 8-9 followed by RUUO after 3 days and simultaneously received estradiol and after one day post RUUO were sacrificed. Group 10-12 followed by RUUO after 3 days and simultaneously received test substances and after 3 days post RUUO were sacrificed. Group 13-14 received test substances followed by RUUO and received test substances again and after 3 days post RUUO were sacrificed.RESULTS: The estradiol reduced body weight significantly (p<0.05) in UUO, and the uterus weight (UW) increased significantly by estradiol (p<0.05). The increased serum levels of blood urea nitrogen (BUN) and creatinine (Cr), and kidney weight (KW) induced by UUO (p<0.05) were not attenuated by estradiol. Estradiol treatment did not alter the levels of BUN, Cr, KW, Cr clearance (CrCl), urine sodium excretion and urine flow when compared with control.CONCLUSION: Although the protective role of estradiol in cardiovascular system is well accepted, however our findings suggest that its protection during UUO or after RUUO in renal system cannot be certain.KEYWORDS: estradiol, ureteral obstruction, renal function, rat

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Acute interstitial nephritis

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0489 ◽

2020 ◽

pp. 4951-4956

Author(s):

Simon D. Roger

Keyword(s):

Renal Function ◽

Interstitial Nephritis ◽

Lupus Erythematosus ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

Sudden Onset ◽

Rapid Decline ◽

Drug Induced ◽

Chronic Renal Impairment ◽

Loin Pain

Acute interstitial nephritis (AIN) is an inflammation of the tubules and interstitium within the kidney, associated with a relatively sudden onset and rapid decline in renal function. It is usually secondary to drugs (antibiotics, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors being most commonly incriminated), with other causes being infections (classically streptococcal, but this is now less common) and immune disorders (systemic lupus erythematosus, sarcoidosis, and tubulointerstitial nephritis with uveitis). Clinical features—the diagnosis of AIN should be considered in any patient with unexplained acute kidney injury. Drug-induced AIN may present with a classic allergic response, including arthralgias, fever, rash, loin pain, and eosinophilia/eosinophiluria, but these are not invariable and their absence does not exclude the diagnosis. The urine typically shows low-grade proteinuria (<1 g/day). Renal biopsy is the only way to confirm or exclude the diagnosis. Management and prognosis—treatment is by ceasing the offending agent, treating the concurrent infectious cause, or managing the immune aetiology with steroids (typically prednisolone 1 mg/kg per day, tapered to zero over 6–8 weeks). Most patients with drug-induced AIN recover renal function, but some are left with chronic renal impairment and a small proportion progress to endstage chronic kidney disease.

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Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury

Clinical Science ◽

10.1042/cs20171625 ◽

2018 ◽

Vol 132 (7) ◽

pp. 825-838 ◽

Cited By ~ 35

Author(s):

Yunwen Yang ◽

Xiaowen Yu ◽

Yue Zhang ◽

Guixia Ding ◽

Chunhua Zhu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Target Genes ◽

Periodic Acid ◽

Kidney Injury ◽

Protective Effects ◽

Low Oxygen ◽

Periodic Acid Schiff ◽

Tubular Cells ◽

Kidney Morphology

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cis-diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro, FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI.

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