scholarly journals Targeting Ferroptosis Attenuates Interstitial Inflammation and Kidney Fibrosis

2021 ◽  
pp. 1-15
Author(s):  
Lu Zhou ◽  
Xian Xue ◽  
Qing Hou ◽  
Chunsun Dai
Keyword(s):  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Kidney Fibrosis ◽  
Ureter Obstruction ◽  
Regulated Necrosis ◽  
Dependent Form

<b><i>Background:</i></b> Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. <b><i>Objectives:</i></b> The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. <b><i>Methods:</i></b> Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. <b><i>Results:</i></b> We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. <b><i>Conclusions:</i></b> This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.

scholarly journals Nicotinamide Mononucleotide Attenuates Renal Interstitial Fibrosis After AKI by Suppressing Tubular DNA Damage and Senescence

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Jia ◽  
Xin Kang ◽  
Lishan Tan ◽  
Yifei Ren ◽  
Lei Qu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Recovery Phase ◽  
Tubular Cell ◽  
Dna Damage And Repair ◽  
Kidney Fibrosis ◽  
Beneficial Effects

Acute kidney injury (AKI) is a worldwide health problem currently lacking therapeutics that directly promote renal repair or prevent the occurrence of chronic fibrosis. DNA damage is a feature of many forms of kidney injury, and targeting DNA damage and repair might be effective strategies for kidney protection in AKI. Boosting nicotinamide adenine dinucleotide (NAD+) levels is thought to have beneficial effects on DNA damage repair and fibrosis in other organs. However, no kidney-related studies of such effects have been performed to date. Here, we have shown that NMN (an NAD+ precursor) administration could significantly reduce tubular cell DNA damage and subsequent cellular senescence induced by hydrogen peroxide and hypoxia in human proximal tubular cells (HK-2 cells). The DNA damage inhibition, antiaging and anti-inflammatory effects of NMN were further confirmed in a unilateral ischemia-reperfusion injury (uIRI) mouse model. Most importantly, the antifibrosis activity of NMN was also shown in ischemic AKI mouse models, regardless of whether NMN was administered in advance or during the recovery phase. Collectively, these results suggest that NMN could significantly inhibit tubular cell DNA damage, senescence and inflammation. NMN administration might be an effective strategy for preventing or treating kidney fibrosis after AKI.

scholarly journals Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment

2019 ◽  
Vol 317 (3) ◽  
pp. F658-F669 ◽  
Author(s):  
Heather M. Perry ◽  
Nicole Görldt ◽  
Sun-sang J. Sung ◽  
Liping Huang ◽  
Kinga P. Rudnicka ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Purinergic Signaling ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Perivascular Cells ◽  
Kidney Fibrosis ◽  
Perivascular Cell ◽  
Persistent Inflammation

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5′-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73−/− kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

The Long Noncoding RNA-H19 Mediates the Progression of Fibrosis from Acute Kidney Injury to Chronic Kidney Disease by Regulating the miR-196a/Wnt/β-Catenin Signaling

Nephron ◽  
2021 ◽  
pp. 1-11
Author(s):  
Xiangnan Dong ◽  
Rui Cao ◽  
Qiang Li ◽  
Lianghong Yin
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Collagen I ◽  
Luciferase Reporter ◽  
Kidney Fibrosis

<b><i>Introduction:</i></b> Long noncoding RNAs (lncRNAs) have been reported to be involved in the occurrence and development of various diseases. This study was to investigate the role of lncRNA-H19 in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) and its underlying mechanism. <b><i>Methods:</i></b> Bilateral renal pedicle ischemia-reperfusion injury (IRI) was used to establish the IRI-AKI model in C57BL/6 mice. The expression levels of lncRNA-H19, miR-196a-5p, α-SMA, collagen I, Wnt1, and β-catenin in mouse kidney tissues and fibroblasts were determined by quantitative real-time PCR and Western blotting. The degree of renal fibrosis was evaluated by hematoxylin and eosin staining. The interaction between lncRNA-H19 and miR-196a-5p was verified by bioinformatics analysis and luciferase reporter assay. Immunohistochemistry and immunofluorescence were used to evaluate the expression of α-SMA and collagen I in kidney tissues and fibroblasts of mice. <b><i>Results:</i></b> lncRNA-H19 is upregulated, and miR-196a-5p is downregulated in kidney tissues of IRI mice. Moreover, miR-196a-5p is a direct target of lncRNA-H19. lncRNA-H19 overexpression promotes kidney fibrosis and activates fibroblasts during AKI-CKD development, while miR-196a-5p overexpression reversed these effects in vitro. Furthermore, lncRNA-H19 overexpression significantly upregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice, while miR-196a-5p overexpression downregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice. <b><i>Conclusion:</i></b> lncRNA-H19 induces kidney fibrosis during AKI-CKD by regulating the miR-196a-5p/Wnt/β-catenin signaling pathway.

scholarly journals Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 306
Author(s):  
Maxime Rossi ◽  
Kéziah Korpak ◽  
Arnaud Doerfler ◽  
Karim Zouaoui Boudjeltia
Keyword(s):  
Reperfusion Injury ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Kidney Injury ◽  
Heme Oxygenase 1

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages.

scholarly journals Regulation of Ferroptosis Pathway by Ubiquitination

2021 ◽  
Vol 9 ◽  
Author(s):  
Xinbo Wang ◽  
Yanjin Wang ◽  
Zan Li ◽  
Jieling Qin ◽  
Ping Wang
Keyword(s):  
Cancer Therapy ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Potential Effect ◽  
26S Proteasome ◽  
Dependent Form ◽  
Intracellular Protein Degradation ◽  
Potential Strategy ◽  
Novel Strategy

Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia–reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. The induction of ferroptosis can be inhibited by sufficient glutathione (GSH) synthesis via system Xc– transporter-mediated cystine uptake. Therefore, induction of ferroptosis by inhibition of cystine uptake or dampening of GSH synthesis has been considered as a novel strategy for cancer therapy, while reversal of ferroptotic effect is able to delay progression of diverse disorders, such as cardiopathy, steatohepatitis, and acute kidney injury. The ubiquitin (Ub)–proteasome pathway (UPP) dominates the majority of intracellular protein degradation by coupling Ub molecules to the lysine residues of protein substrate, which is subsequently recognized by the 26S proteasome for degradation. Ubiquitination is crucially involved in a variety of physiological and pathological processes. Modulation of ubiquitination system has been exhibited to be a potential strategy for cancer treatment. Currently, more and more emerged evidence has demonstrated that ubiquitous modification is involved in ferroptosis and dominates the vulnerability to ferroptosis in multiple types of cancer. In this review, we will summarize the current findings of ferroptosis surrounding the viewpoint of ubiquitination regulation. Furthermore, we also highlight the potential effect of ubiquitination modulation on the perspective of ferroptosis-targeted cancer therapy.

Abstract P298: Finerenone Protects Against the Acute and Chronic Consequences of Renal Ischemia/reperfusion Injury

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jonatan Barrera-Chimal ◽  
Alan Le Mercier ◽  
Soumaya El-Moghrabi ◽  
Peter Kolkhof ◽  
Frederic Jaisser
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Left Kidney ◽  
Kidney Injury ◽  
Fold Increase ◽  
Renal Ischemia ◽  
Mrna Levels ◽  
Beneficial Effects ◽  
The Right

Introduction: One of the most common causes of acute kidney injury (AKI) is renal ischemia/reperfusion (IR). Mineralocorticoid receptor (MR) antagonism has shown beneficial effects against renal IR consequences. The potential benefit of novel non-steroidal MR antagonists such as finerenone has not been explored. Objective: Evaluate the efficacy of finerenone to prevent the acute and chronic consequences of ischemic AKI. Methods: For the acute study (24 hours), 18 rats were divided in: sham, rats subjected to bilateral renal ischemia of 25 min and rats that received three doses of finerenone at -48 h, -24 h and -1 h before the ischemia. For the chronic study (4 months), 21 rats were divided in: sham, rats with 45 min of bilateral ischemia and rats treated with Finerenone at day -2, -1 and 1h before IR. The left kidney was used for histology and the right kidney for molecular analysis. Results: After 24 h of reperfusion, the untreated IR rats presented a 3-fold increase in plasma creatinine, accompanied by 40% of tubules presenting cell detachment and casts. Kim-1 and NGAL mRNA levels were induced by 30-fold. In contrast, the rats that received finerenone presented normal creatinine and significantly fewer injured tubules (11%) and a less pronounced induction of kim-1 and NGAL (8-fold). After 4 months, the untreated IR rats developed chronic kidney disease (CKD), evidenced by kidney dysfunction, increased proteinuria (121.6 vs. 14.3 mg/24h in sham) and renal vascular resistance (16.8 vs. 11.4 mmHg/mL in sham). Tubular dilation, extensive tubule-interstitial fibrosis and an increase in kidney TGF-β and Collagen-I mRNA levels also characterized CKD. The transition from AKI to CKD was fully prevented by finerenone administration at the time of IR. Conclusion: Altogether, our data shows that finerenone is able to prevent AKI induced by IR as well as the chronic and progressive deterioration of kidney function and structure.

scholarly journals A two-stage bilateral ischemia-reperfusion injury-induced AKI to CKD transition model in mice

2020 ◽  
Vol 319 (2) ◽  
pp. F304-F311
Author(s):  
Jie Zhang ◽  
Ximing Wang ◽  
Jin Wei ◽  
Lei Wang ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Subsequent Development ◽  
Two Stage ◽  
New Model ◽  
Contralateral Kidney ◽  
Survival Threshold

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD). Recently, our laboratory generated a mouse model with the typical phenotypes of AKI to CKD transition in the unilateral kidney. However, AKI, CKD, and even the transition from AKI to CKD usually occur bilaterally rather than unilaterally in patients. Therefore, in the present study, we further modified the strategy and developed a new model of CKD transitioned from bilateral ischemia-reperfusion injury (IRI) in C57BL/6 mice. In this new model, unilateral severe IRI was performed in one kidney while the contralateral kidney was kept intact to maintain animal survival; then, following 14 days of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was subjected to a similar IRI. Animals of these two-stage bilateral IRI models with pedicle clamping of 21 and 24 min at a body temperature of 37°C exhibited incomplete recovery from AKI and subsequent development of CKD with characteristics of progressive decline in glomerular filtration rate, increases in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis, in both kidneys. In conclusion, a new bilateral AKI to CKD transition animal model with a typical phenotype of CKD was generated in C57BL/6 mice.

scholarly journals Ferroptosis in Liver Diseases: An Overview

2020 ◽  
Vol 21 (14) ◽  
pp. 4908 ◽  
Author(s):  
Martina Maria Capelletti ◽  
Hana Manceau ◽  
Hervé Puy ◽  
Katell Peoc’h
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Ischemia Reperfusion Injury ◽  
Primary Liver Cancer ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Redox Active ◽  
Dependent Form ◽  
Repair Activity

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia–reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

scholarly journals Mouse Models of Acute Kidney Injury

2021 ◽  
Author(s):  
Navjot Pabla ◽  
Yogesh Scindia ◽  
Joseph Gigliotti ◽  
Amandeep Bajwa
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Mouse Models ◽  
Poor Prognosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Cecal Ligation And Puncture ◽  
High Degree

Acute Kidney Injury (AKI) is a poor prognosis in hospitalized patients that is associated with high degree of mortality. AKI is also a major risk factor for development of chronic kidney disease. Despite these serious complications associated with AKI there has not been a great amount of progress made over the last half-century. Here we have outlined and provided details on variety of mouse models of AKI. Some of the mouse models of AKI are renal pedicle clamping (ischemia reperfusion injury), Cisplatin induced nephrotoxicity, sepsis (LPS, cecal slurry, and cecal ligation and puncture), folic acid, and rhabdomyolysis. In this chapter we describe in detail the protocols that are used in our laboratories.

scholarly journals Acute kidney injury induces hallmarks of polycystic kidney disease

2016 ◽  
Vol 311 (4) ◽  
pp. F740-F751 ◽  
Author(s):  
Almira Kurbegovic ◽  
Marie Trudel
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Polycystic Kidney ◽  
Stimulation Of

Acute kidney injury (AKI) and autosomal dominant polycystic kidney disease (ADPKD) are considered separate entities that both frequently cause renal failure. Since ADPKD appears to depend on a polycystin-1 (Pc1) or Pc2 dosage mechanism, we investigated whether slow progression of cystogenesis in two Pkd1 transgenic mouse models can be accelerated with moderate ischemia-reperfusion injury (IRI). Transient unilateral left ischemic kidneys in both nontransgenic and transgenic mice reproducibly develop tubular dilatations, cysts, and typical PKD cellular defects within 3 mo post-IRI. Similar onset and severity of IRI induced-cystogenesis independently of genotype revealed that IRI is sufficient to promote renal cyst formation; however, this response was not further amplified by the transgene in Pkd1 mouse models. The IRI nontransgenic and transgenic kidneys showed from 16 days post-IRI strikingly increased and sustained Pkd1/Pc1 (>3-fold) and Pc2 (>8-fold) expression that can individually be cystogenic in mice. In parallel, long-term and important stimulation of hypoxia-inducible factor 1α expression was induced as in polycystic kidney disease. While mammalian target of rapamycin signaling is activated, stimulation of the Wnt pathway, with markedly increased active β-catenin and c-Myc expression in IRI renal epithelium, uncovered a similar regulatory cystogenic response shared by IRI and ADPKD. Our study demonstrates that long-term AKI induces cystogenesis and cross talk with ADPKD Pc1/Pc2 pathogenic signaling.

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