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

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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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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An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity

International Journal of Molecular Sciences ◽

10.3390/ijms22157975 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7975

Author(s):

Saioa Gómez-Zorita ◽

Iñaki Milton-Laskibar ◽

Laura García-Arellano ◽

Marcela González ◽

María P. Portillo

Keyword(s):

Adipose Tissue ◽

Protective Role ◽

Inflammatory Factors ◽

Current Evidence ◽

Disease Outcomes ◽

Lower Activation ◽

Two Factors ◽

Obese Subjects ◽

Ace2 Gene

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.

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P0523PROTECTIVE ROLE OF REGULATORY B CELLS ON THE RENAL TISSUE REPAIRMEN AFTER ISCHEMIA REPERCUSSION INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0523 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yokota Yunosuke ◽

Goh Kodama ◽

Sakuya Itou ◽

Yosuke Nakayama ◽

Nobukazu Komatsu ◽

...

Keyword(s):

Flow Cytometry ◽

Renal Function ◽

B Cells ◽

Interleukin 10 ◽

Renal Tissue ◽

Protective Role ◽

Regulatory B Cells ◽

Tubulointerstitial Injury ◽

Iri Model

Abstract Background and Aims Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end- stage renal disease. It has been postulated that interleukin-10 (IL-10)-producing Regulatory B cells (Breg) play an important role for the tissue repairment in several tissues and organs. Basically, protective role of Breg has been reported in inflammatory bowel disease. In the kidney, it has been shown that IL-10 suppresses renal function decline and improves renal prognosis in IRI model, a typical model of AKI. However, the identity of Breg in the kidney and their origin have not been clarified. Further, how the Breg works during the transition from AKI to CKD is not known. Therefore, first we investigated whether Breg existed in renal tissue on the progression from AKI to CKD in IRI model mice. Further, we performed splenectomy, and examined the renal injury, Breg, and plasma IL-10 levels in this model. Method To examine the existence of Breg in the kidney of IRI model, we used 8-10 weeks-old GFP / IL-10 mice based on C57BL / 6J mice. They are reporter mice for IL-10 producing cells, and can visualize IL-10 producing cells under a fluorescence microscope without fluorescent immunostaining. We prepared following three groups, sham, IRI (unilateral), and IRI + SN (splenectomy) groups. Mice were anesthetized with chloral hydrate (4 g/kg,, intraperitoneal). After making a midline incision, exposed a blood vessel of the left renal pedicles and clamped it for 30 min by clips. one day, 7 days, and 14 days after the surgery, mice were sacrificed, and renal function and plasma IL-10 levels as well as tissue damages by PAS and Masson’s Trichrome staining were assessed. Tissue IL-10-producing cells were detected by flow cytometry. Results There was no difference of plasma IL-10 levels and renal tubulointerstitial injury in IRI group and IRI+SN group on day 1 after IRI. However, on day 7 and day 14, plasma IL-10 levels became gradually higher in IRI group, and SN decreased the increase in IL-10 levels. Tubulointerstitial injury was induced by IRI and SN further worsened tubular damages. Serum Cr and BUN levels were not different in three groups due to normal right kidney. On day 1, number of IL-10-producing B cells increased in the spleen and renal medulla in IRI group confirmed by flow cytometry, which was completely diminished by SN, suggesting that origin of the infiltrated Breg might be spleen, thereby being involved in the protective role in IRI injury in the kidney. Conclusion We report for the first time that Breg might be recruited from spleen by AKI, which may be one of the mechanisms to prevent the progression to CKD.

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A review of oxidative stress in acute kidney injury: protective role of medicinal plants-derived antioxidants

African Journal of Traditional Complementary and Alternative Medicines ◽

10.4314/ajtcam.v10i4.15 ◽

2013 ◽

Vol 10 (4) ◽

Cited By ~ 1

Author(s):

S Palipoch

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Medicinal Plants ◽

Kidney Injury ◽

Protective Role

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Protective Role of Conization Before Radical Hysterectomy in Early-Stage Cervical Cancer: A Propensity-Score Matching Study

Annals of Surgical Oncology ◽

10.1245/s10434-021-09695-4 ◽

2021 ◽

Author(s):

Nicolò Bizzarri ◽

Luigi Pedone Anchora ◽

Ali Kucukmetin ◽

Nithya Ratnavelu ◽

Porfyrios Korompelis ◽

...

Keyword(s):

Cervical Cancer ◽

Propensity Score ◽

Propensity Score Matching ◽

Radical Hysterectomy ◽

Early Stage ◽

Protective Role ◽

Early Stage Cervical Cancer

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

Mediators of Inflammation ◽

10.1155/2020/2120971 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Naren Bao ◽

Di Dai

Keyword(s):

Renal Function ◽

Kidney Injury ◽

Serum Levels ◽

Protective Role ◽

Sudden Onset ◽

Clinical Syndrome ◽

Ischemia And Reperfusion ◽

Oxygen Species ◽

Kidney Tubules ◽

Tubular Cells

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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Potential role of imaging for assessing acute pancreatitis-induced acute kidney injury

British Journal of Radiology ◽

10.1259/bjr.20200802 ◽

2020 ◽

pp. 20200802

Author(s):

Yi Wang ◽

Kaixiang Liu ◽

Xisheng Xie ◽

Bin Song

Keyword(s):

Acute Kidney Injury ◽

Acute Pancreatitis ◽

Early Stage ◽

Kidney Injury ◽

Current Evidence ◽

Advanced Imaging ◽

Creatinine Concentration ◽

New Techniques ◽

Magnetic Resonance Imaging Mri

Acute kidney injury (AKI) is a common complication of acute pancreatitis (AP) that is associated with increased mortality. Conventional assessment of AKI is based on changes in serum creatinine concentration and urinary output. However, these examinations have limited accuracy and sensitivity for the diagnosis of early-stage AKI. This review summarizes current evidence on the use of advanced imaging approaches and artificial intelligence (AI) for the early prediction and diagnosis of AKI in patients with AP. CT scores, CT post-processing technology, Doppler ultrasound, and AI technology provide increasingly valuable information for the diagnosis of AP-induced AKI. Magnetic resonance imaging (MRI) also has potential for the evaluation of AP-induced AKI. For the accurate diagnosis of early-stage AP-induced AKI, more studies are needed that use these new techniques and that use AI in combination with advanced imaging technologies.

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Stanniocalcin-1 Alleviates Contrast-Induced Acute Kidney Injury by Regulating Mitochondrial Quality Control via the Nrf2 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1898213 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 3

Author(s):

Fei Zhao ◽

Li-Xin Feng ◽

Qian Liu ◽

Hong-Shen Wang ◽

Cheng-Yuan Tang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Quality Control ◽

Kidney Injury ◽

Protective Role ◽

Mitochondrial Quality Control ◽

Therapy Strategy ◽

Nrf2 Signaling Pathway ◽

Short And Long Term ◽

Renal Tubular

Contrast-induced acute kidney injury (CI-AKI) is the third common cause of acute kidney injury (AKI), which is associated with poor short- and long-term outcomes. Currently, effective therapy strategy for CI-AKI remains lacking. Stanniocalcin-1 (STC1) is a conserved glycoprotein with antiapoptosis and anti-inflammatory functions, but the role of STC1 in controlling CI-AKI is unknown. Here, we demonstrated a protective role of STC1 in contrast-induced injury in cultured renal tubular epithelial cells and CI-AKI rat models. Recombinant human STC1 (rhSTC1) regulated mitochondrial quality control, thus suppressing contrast-induced mitochondrial damage, oxidative stress, inflammatory response, and apoptotic injury. Mechanistically, activation of the Nrf2 signaling pathway contributes critically to the renoprotective effect of STC1. Together, this study demonstrates a novel role of STC1 in preventing CI-AKI and reveals Nrf2 as a molecular target of STC1. Therefore, this study provides a promising preventive target for the treatment of CI-AKI.

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