scholarly journals Effect of NAD+ boosting on kidney ischemia-reperfusion injury

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252554
Author(s):  
Marya Morevati ◽  
Søren Egstrand ◽  
Anders Nordholm ◽  
Maria L. Mace ◽  
Claus B. Andersen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Mitochondrial Homeostasis ◽  
Prophylactic Administration ◽  
Increased Risk ◽  
Renal Tubular

Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD+) with progressing fibrosis resulting in CKD. NAD+ is a co-enzyme for several proteins, including the NAD+ dependent sirtuins. NAD+ augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD+, caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin (postn) and Inhibin subunit beta-A, (activin A / Inhba), both 24 hours and 14 days after surgery. NR restored tissue NAD+ to that of the sham group, increased autophagy (reduced p62) and sirtuin1 (Sirt1) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD+ depletion and impaired autophagy, while augmentation of NAD+ by NR restored tissue NAD+ and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis.

scholarly journals P0539NICOTIFLORIN ATTENUATES RENAL ISCHEMIA/REPERFUSION INJURY THROUGH REDUCING CELL APOPTOSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Lin Wang ◽  
Yan Xu
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Abstract Background and Aims Renal ischemia/reperfusion (I/R) is the main cause for acute kidney injury, Nicotiflorin can ameliorate ischemia/reperfusion injury in other organs, just like in cerebral ischemic damage. Therefore, this article intends to explore whether Nicotiflorin has protective effects on renal tubular epithelial cell after ischemia-reperfusion. On the one hand, We use C57 mice to establish the Nicotiflorin group, DMSO group, AKI group, sham group and control group to investigate whether Nicotiflorin can ameliorate ischemia-reperfusion injury of kidney. In other hand, we use CCK8 to explore the optimal concentration of Nicotiflorin in renal tubular epithelial cells and find optimal hypoxia oxygenation time, in order to analysis the influence of Nicotiflorin. The results indicate that Nicotiflorin can alleviate ischemia-reperfusion injury by reducing apoptosis of renal tubular epithelial cells. Method In this study, we investigated the protective mechanism of Nicotiflorin on ischemic acute kidney injury by analyzing gene chip in patients with acute kidney injury and proving in vitro and in vivo experiments. The main methods are as follows: (1) Multiple nucleus ischemia-reperfusion model transcriptase data were selected from the NCBI GEO Datasets database and analyzed to screen out related proteins that may be involved in ischemia-reperfusion kidney injury; (2) The tertiary structure of Nicotiflorin and related proteins was obtained from the SWISS-MODEL database and the PubChem compound database. The molecular docking between protein and Nicotiflorin was performed using Autodock software, and the binding energy between Nicotiflorin and the selected protein was analyzed to determine Nicotiflorin binds to each other; (3) We set different groups, such as control group, sham group, AKI group, Nicotiflorin group and DMSO group in animals. The blood function was used to detect renal injury related function indicators 24 hours after modeling. Renal tissue samples were collected for real-time fluorescent RT-PCR, Western blotting and histopathological analysis; (4)Renal tubular epithelial cells were treated with different concentrations of Nicotiflorin, CCK8 was screened for the most appropriate concentration, and the hypoxic and reoxygenated cells were intervened at the concentration to explore the interaction between Nicotiflorin and the docking protein, and to observe the protective mechanism of Nicotiflorin on the kidney Results Conclusion Nicotiflorin binds to ATF3 and promotes the expression of Cyr61 through protein interactions to improve renal ischemia-reperfusion injury.

Promotion of cell proliferation by clusterin in the renal tissue repair phase after ischemia-reperfusion injury

2014 ◽  
Vol 306 (7) ◽  
pp. F724-F733 ◽  
Author(s):  
Christopher Y. C. Nguan ◽  
Qiunong Guan ◽  
Martin E. Gleave ◽  
Caigan Du
Keyword(s):  
Cell Proliferation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Repair ◽  
Renal Tubular ◽  
Repair Phase

Renal repair begins soon after the kidney suffers ischemia-reperfusion injury (IRI); however, its molecular pathways are not fully understood. Clusterin (Clu) is a chaperone protein with cytoprotective functions in renal IRI. The aim of this study was to investigate the role of Clu in renal repair after IRI. IRI was induced in the left kidneys of wild-type (WT) C57BL/6J (B6) vs. Clu knockout (KO) B6 mice by clamping the renal pedicles for 28–45 min at the body temperature of 32°C. The renal repair was assessed by histology and confirmed by renal function. Gene expression was examined using PCR array. Here, we show that following IRI, renal tubular damage and Clu expression in WT kidneys were induced at day 1, reached the maximum at day 3, and significantly diminished at day 7 along with normal function, whereas the tubular damage in Clu KO kidneys steadily increased from initiation of insult to the end of the experiment, when renal failure occurred. Renal repair in WT kidneys was positively correlated with an increase in Ki67+ proliferative tubular cells and survival from IRI. The functions of Clu in renal repair and renal tubular cell proliferation in cultures were associated with upregulation of a panel of genes that could positively regulate cell cycle progression and DNA damage repair, which might promote cell proliferation but not involve cell migration. In conclusion, these data suggest that Clu is required for renal tissue regeneration in the kidney repair phase after IRI, which is associated with promotion of tubular cell proliferation.

1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose from Galla rhois Ameliorates Renal Tubular Injury and Microvascular Inflammation in Acute Kidney Injury Rats

2018 ◽  
Vol 46 (04) ◽  
pp. 785-800 ◽  
Author(s):  
Ji Hun Park ◽  
Min Chol Kho ◽  
Hyun Cheol Oh ◽  
Youn Chul Kim ◽  
Jung Joo Yoon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Urine Volume ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Tubular Dysfunction ◽  
Tubular Injury ◽  
Microvascular Inflammation ◽  
Renal Tubular

Renal ischemia-reperfusion injury (IRI), an important cause of acute kidney injury (AKI), causes increased renal tubular injury and microvascular inflammation. 1,[Formula: see text]2,[Formula: see text]3,[Formula: see text]4,[Formula: see text]6-penta-O-galloyl-[Formula: see text]-D-glucose (PGG) from Galla rhois has anticancer, anti-oxidation and angiogenesis effects. We examined protective effects of PGG on IRI-induced acute AKI. Clamping both renal arteries for 45[Formula: see text]min induced isechemia and then reperfusion. Treatment with PGG (10[Formula: see text]mg/kg/day and 50[Formula: see text]mg/kg/day for four days) significantly ameliorated urine volume, urine osmolality, creatinine clearance (Ccr) and blood urea nitrogen (BUN). In addition, PGG increased aquaporine 1/2/3, Na[Formula: see text]-K[Formula: see text]-ATPase and urea transporter (UT-B) and decreased ICAM-1, MCP-1, and HMGB-1 expression. In this histopathologic study, PGG improved glomerular and tubular damage. Immunohistochemistry results showed that PGG increased aquaporine 1/2, and Na[Formula: see text]-K[Formula: see text] ATPase and decreased ICAM-1 expression. These findings suggest that PGG ameliorates tubular injury including tubular dysfunction and microvascular inflammation in IRI-induced AKI rats.

scholarly journals Kynurenine 3-monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury

2018 ◽  
Author(s):  
Xiaozhong Zheng ◽  
Ailiang Zhang ◽  
Margaret Binnie ◽  
Kris McGuire ◽  
Scott P Webster ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Multiple Organ ◽  
Biologically Active ◽  
Renal Tubular Cell ◽  
Renal Tubular

SUMMARYAcute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.

Abstract 193: Antithrombin Perfluorocarbon Nanoparticles Ameliorate Renal Injury Following Transient Warm Ischemia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Chandu Vemuri ◽  
Junjie Chen ◽  
Rohun U Palekar ◽  
John S Allen ◽  
Xiaoxia Yang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Warm Ischemia ◽  
P Value ◽  
Sprague Dawley ◽  
Histologic Analysis ◽  
Microvascular Thrombosis

Objective: Thrombin mediated microvascular thrombosis plays a crucial role in the pathogenesis of acute renal reperfusion injury following transient ischemia. We hypothesize that anti-thrombin nanoparticles will ameliorate acute renal injury by inhibiting microvascular thrombosis. Methods: Adult, male Sprague Dawley rats were randomized into two groups of 5 to receive tail vein injections of saline or nanoparticles loaded with Phe[D]-Pro-Arg-Chloromethylketone (NP-PPACK). Immediately following injection, all animals underwent operative bilateral renal artery occlusion to create 45 minutes of warm ischemia, followed by restoration of renal blood flow. Blood samples were drawn daily and animals were euthanized on day 1 or 7 for histologic analysis of kidney injury (H&E, TUNEL and thrombin staining). Results: Histologic analysis of renal tissue revealed significant apoptosis, necrosis and thrombin accumulation 1 day after ischemia-reperfusion, confirming acute kidney injury. The peak creatinine (mg/dl) on day 1 was significantly lower in NP-PPACK treated animals (0.57 +/- 0.07 (SEM)) than in saline treated controls (1.40 +/- 0.20 (SEM); p-value <0.01). Furthermore, animals treated with NP-PPACK continued to exhibit less renal dysfunction for 7 days after injury (Figure 1). Conclusion: Histologically confirmed intrarenal thrombosis was detected one day after ischemia-reperfusion injury. Targeted inhibition of thrombin with NP-PPACK prevented a decline in renal function following transient occlusion. Future work will focus on defining the underlying mechanisms of this effect.

scholarly journals Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽  
2021 ◽  
Author(s):  
Taro Miyagawa ◽  
Yasunori Iwata ◽  
Megumi Oshima ◽  
Hisayuki Ogura ◽  
Koichi Sato ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Advanced Glycation End Products ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Advanced Glycation ◽  
Renal Tubular Damage ◽  
Glycation End Products ◽  
End Products ◽  
Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

P0516DCR2 PROMOTES RENAL FIBROSIS BY ACCELERATING TUBULAR CELL SENESCENCE AFTER ISCHEMIA REPERFUSION INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jia Chen ◽  
Yani He
Keyword(s):  
Reperfusion Injury ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Senescence ◽  
Tubular Cell ◽  
Renal Tubules ◽  
Senescent Phenotype ◽  
Renal Tubular

Abstract Background and Aims Cell senescence of renal tubular epithelial cells (RTECs), which is involved in renal fibrosis, is a key event in the progression of acute kidney injury (AKI). However, the underlying mechanism remains unclear. This study aims to investigate the role and mechanism of decoy receptor 2 (DcR2) in renal fibrosis and cell senescence of RTECs. Method KSP-creDcR2f/f mouse (Tubular DcR2 KO) and Ischemia-Reperfusion (I/R) Injury models were constructed. The models were divided into moderated (ischemia 20min) and severe (ischemia 35min) injury. The expression of renal DcR2, senescent markers (P16, P21, SA-β-gal) and senescent phenotype (IL-6, TGF-β1) were detected. Furthermore, wild type (WT) mice and KSP-creDcR2f/f mice were used to compare the degree of renal tissue and functional damage and the senescence of renal tubular cells after I/R injury. In vitro, knockdown and overexpression experiments were performed by transfected DcR2 siRNA or overexpressed adenovirus in hypoxia-reoxygenation stimulated mouse primary RTEC. The cell senescence and phenotype markers were further detected. Results The levels of Scr, BUN and urinary DcR2 and renal injury scores were significantly increased in I/R group at the early stage (1d) of renal injury compared with sham group. Renal fibrosis was observed in the later stage (21-42d) in severe injury. DcR2 was mainly expressed in renal tubules, and the percentage of tubular DcR2 was increased after I/R injury. DcR2 was co-expressed with P16 and SA-β-gal, and urinary DcR2 levels were related to senescent makers, suggesting that DcR2 was associated with cell senescence. The renal function and renal injury scores were lower in KSP-creDcR2f/f mice than that of WT after renal reperfusion. And the area of renal fibrosis was significantly decreased in KSP-creDcR2f/f mice compared with WT, indicating DcR2 inhibited renal fibrosis. Furthermore, the expression of senescent phenotype were suppressed in tubular DcR2 KO mice after I/R injury, suggesting that DcR2 could promote the senescence of renal tubule cells. Conclusion DcR2 promotes renal fibrosis by accelerating tubular cell senescence after ischemia-reperfusion Injury, suggesting that DcR2 may be a potential intervention target during the progression of AKI.

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