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 Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

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 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.

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 DNA repair in ischemic acute kidney injury

2017 ◽  
Vol 312 (4) ◽  
pp. F551-F555 ◽  
Author(s):  
Jeffrey D. Pressly ◽  
Frank Park
Keyword(s):  
Dna Damage ◽  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
The Body ◽  
Negative Effects ◽  
Dna Damage And Repair ◽  
Dna Strand ◽  
Cellular Dna

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury leading to an induction of oxidative stress, cellular dysfunction, and loss of renal function. DNA damage, including oxidative base modifications and physical DNA strand breaks, is a consequence of renal IRI. Like many other organs in the body, a redundant and highly conserved set of endogenous repair pathways have evolved to selectively recognize the various types of cellular DNA damage and combat its negative effects on cell viability. Severe damage to the DNA, however, can trigger cell death and elimination of the injured tubular epithelial cells. In this minireview, we summarize the state of the current field of DNA damage and repair in the kidney and provide some expected and, in some cases, unexpected effects of IRI on DNA damage and repair in the kidney. These findings may be applicable to other forms of acute kidney injury and could provide new opportunities for renal research.

scholarly journals Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 271
Author(s):  
Khai Gene Leong ◽  
Elyce Ozols ◽  
John Kanellis ◽  
Shawn S. Badal ◽  
John T. Liles ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

scholarly journals Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

2020 ◽  
Author(s):  
Caitriona M. McEvoy ◽  
Sergi Clotet-Freixas ◽  
Tomas Tokar ◽  
Chiara Pastrello ◽  
Shelby Reid ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Kidney Injury ◽  
Tca Cycle ◽  
Proteomics Analysis ◽  
Beneficial Effects ◽  
Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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.

DNA damage and repair in human spinal cord following ischemia–reperfusion injury

2006 ◽  
Vol 1 (2) ◽  
pp. 141-145
Author(s):  
Glen Roseborough ◽  
Ruxian Lin ◽  
Daqing Gao ◽  
Amy McHale ◽  
Lei Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dna Damage ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dna Damage And Repair ◽  
Human Spinal Cord
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