scholarly journals NLRP3 associated with chronic kidney disease progression after ischemia/reperfusion-induced acute kidney injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhihuang Zheng ◽  
Kexin Xu ◽  
Chuanlei Li ◽  
Chenyang Qi ◽  
Yili Fang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Immune Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Chronic Phase ◽  
Kidney Injury ◽  
Receptor Protein ◽  
Tubular Damage

AbstractNod-like receptor protein 3 (NLRP3), as an inflammatory regulator, has been implicated in acute kidney injury (AKI). Failed recovery after AKI can lead to chronic kidney disease (CKD). However, the role of NLRP3 in the AKI-CKD transition is still unknown. A mild or severe AKI mouse model was performed by using ischemia-reperfusion injury (IRI). We evaluated the renal NLRP3 expression in acute and chronic phases of ischemic AKI, respectively. Although serum creatinine (Cr) and blood urea nitrogen (BUN) levels in AKI chronic phase were equivalent to normal baseline, histological analysis and fibrotic markers revealed that severe AKI-induced maladaptive tubular repair with immune cell infiltration and fibrosis. Tubular damage was restored completely in mild AKI rather than in severe AKI. Of note, persistent overexpression of NLRP3 was also found in severe AKI but not in mild AKI. In the severe AKI-induced chronic phase, there was a long-term high level of NLRP3 in serum or urine. Overt NLRP3 was mainly distributed in the abnormal tubules surrounded by inflammatory infiltrates and fibrosis, which indicated the maladaptive repair. Renal Nlrp3 overexpression was correlated with infiltrating macrophages and fibrosis. Renal NLRP3 signaling-associated genes were upregulated after severe AKI by RNA-sequencing. Furthermore, NLRP3 was found increased in renal tubular epitheliums from CKD biopsies. Together, persistent NLRP3 overexpression was associated with chronic pathological changes following AKI, which might be a new biomarker for evaluating the possibility of AKI-CKD transition.

scholarly journals Huaier Extract Attenuates Acute Kidney Injury to Chronic Kidney Disease Transition by Inhibiting Endoplasmic Reticulum Stress and Apoptosis via miR-1271 Upregulation

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Jing-Ying Zhao ◽  
Yu-Bin Wu
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Endoplasmic Reticulum Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury

Endoplasmic reticulum stress (ERS) is strongly associated with acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Huaier extract (HE) protects against kidney injury; albeit, the underlying mechanism is unknown. We hypothesized that HE reduces kidney injury by inhibiting ERS. In this study, using an AKI-CKD mouse model of ischemia-reperfusion injury (IRI), we evaluated the effect of HE on AKI-CKD transition. We also explored the underlying molecular mechanisms in this animal model and in the HK-2 human kidney cell line. The results showed that HE treatment improved the renal function, demonstrated by a significant decrease in serum creatinine levels after IRI. HE appreciably reduced the degree of kidney injury and fibrosis and restored the expression of the microRNA miR-1271 after IRI. Furthermore, HE reduced the expression of ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and inhibited apoptosis in the IRI group. This in vivo effect was supported by in vitro results in which HE inhibited apoptosis and decreased the expression of CHOP and GRP78 induced by ERS. We demonstrated that CHOP is a target of miR-1271. In conclusion, HE reduces kidney injury, probably by inhibiting apoptosis and decreasing the expression of GRP78 and CHOP via miR-1271 upregulation.

scholarly journals New mouse model of chronic kidney disease transitioned from ischemic acute kidney injury

2019 ◽  
Vol 317 (2) ◽  
pp. F286-F295 ◽  
Author(s):  
Jin Wei ◽  
Jie Zhang ◽  
Lei Wang ◽  
Shan Jiang ◽  
Liying Fu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Reperfusion Injury ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD), which is closely associated with the severity of AKI. However, the underlying mechanisms for the AKI to CKD transition remain unclear. Several animal models with AKI to CKD transition have been generated and widely used in research; however, none of them exhibit the typical changes in glomerular filtration rate or plasma creatinine, the hallmarks of CKD. In the present study, we developed a novel model with a typical phenotype of AKI to CKD transition in C57BL/6 mice. In this model, life-threatening ischemia-reperfusion injury was performed in one kidney, whereas the contralateral kidney was kept intact to maintain animal survival; then, after 2 wk of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was removed. Animals of this two-stage unilateral ischemia-reperfusion injury model with pedicle clamping of 21 and 24 min exhibited an incomplete recovery from AKI and subsequent progression of CKD with characteristics of a progressive decline in glomerular filtration rate, increase in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis. In conclusion, a new model of the AKI to CKD transition was generated in C57BL/6 mice.

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 Exogenous Wnt1 Prevents Acute Kidney Injury and Its Subsequent Progression to Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Hong ◽  
Yanni Zhou ◽  
Dedong Wang ◽  
Fuping Lyu ◽  
Tianjun Guan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Blood Biochemical

Studies suggest that Wnt/β-catenin agonists are beneficial in the treatment of acute kidney injury (AKI); however, it remains elusive about its role in the prevention of AKI and its progression to chronic kidney disease (CKD). In this study, renal Wnt/β-catenin signaling was either activated by overexpression of exogenous Wnt1 or inhibited by administration with ICG-001, a small molecule inhibitor of β-catenin signaling, before mice were subjected to ischemia/reperfusion injury (IRI) to induce AKI and subsequent CKD. Our results showed that in vivo expression of exogenous Wnt1 before IR protected mice against AKI, and impeded the progression of AKI to CKD in mice, as evidenced by both blood biochemical and kidney histological analyses. In contrast, pre-treatment of ICG-001 before IR had no effect on renal Wnt/β-catenin signaling or the progression of AKI to CKD. Mechanistically, in vivo expression of exogenous Wnt1 before IR suppressed the expression of proapoptotic proteins in AKI mice, and reduced inflammatory responses in both AKI and CKD mice. Additionally, exogenous Wnt1 inhibited apoptosis of tubular cells induced by hypoxia-reoxygenation (H/R) treatment in vitro. To conclude, the present study provides evidences to support the preventive effect of Wnt/β-catenin activation on IR-related AKI and its subsequent progression to CKD.

scholarly journals P0689LINACLOTIDE, THE GUANYLATE CYCLASE C AGONIST LIMITS CARDIAC FIBROSIS FORMATION IN MICE WITH CHRONIC KIDNEY DISEASE AFTER ISCHEMIA-REPERFUSION INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Naohito Isoyama ◽  
Yuki Nakayama ◽  
Kimihiko Nakamura ◽  
Toshiya Hiroyoshi ◽  
Kouki Fujikawa ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Reperfusion Injury ◽  
Western Blotting ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Chronic Phase ◽  
Kidney Injury ◽  
Expression Level

Abstract Background and Aims Cardiovascular disease (CVD) is a major cause of mortality in patients with chronic kidney disease (CKD). Renal ischemia-reperfusion injury (IRI) is a clinically significant condition that progress to CKD after acute kidney injury (AKI). We have reported that the suppression of Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine, by linaclotide could prevent renal fibrosis and improve renal function in the chronic phase after renal IRI. TMAO has been linked directly with progression of CVD too. We investigated whether the reduction of TMAO by linaclotide limits cardiac fibrosis in mouse model of CKD after IRI. Method Linaclotide (100μg/kg) was administered for 2weeks before IRI and continued for 2weeks after IRI. After 2weeks since IRI, removed hearts sections were performed Azan stain to evaluate the level of fibrosis and western blotting to evaluate the expression level of fibronectin. Results The administration of linaclotide significantly improved cardiac fibrosis area (Fig1). Additionally, western blotting showed linaclotide suppress the expression level of fibronectin (Fig2). Conclusion The reduction of TMAO by linaclotide could prevent cardiac fibrosis in the chronic phase after renal IRI. Linaclotide may be a powerful tool for prevention of the cardiorenal syndrome after renal IRI.

scholarly journals Long-term outcomes in mouse models of ischemia-reperfusion-induced acute kidney injury

2019 ◽  
Vol 317 (4) ◽  
pp. F1068-F1080 ◽  
Author(s):  
Lauren Scarfe ◽  
Anna Menshikh ◽  
Emily Newton ◽  
Yuantee Zhu ◽  
Rachel Delgado ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Strains ◽  
Preclinical Studies ◽  
Long Term Outcomes

Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.

scholarly journals Orai1: A New Therapeutic Target for the Acute Kidney Injury-to-Chronic Kidney Disease Transition

Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
David P. Basile ◽  
Jason A. Collett
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Acute Injury ◽  
Chronic Kidney Injury ◽  
Sustained Increase

This review focuses on the potential mediation in the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition by lymphocytes. We highlight evidence that lymphocytes, particularly Th17 cells, modulate the severity of both acute injury and chronic kidney disease. Th17 cells are strongly influenced by the activity of the store-operated Ca<sup>2+</sup>channel Orai1, which is upregulated on lymphocytes in animal models of AKI. Inhibition of this channel attenuates both acute and chronic kidney injury in rodent models. In addition, Oria1+ cells are increased in peripheral blood of patients with AKI. Similarly, peripheral blood cells manifest an early and sustained increase in Orai1 expression in a rat model of ischemia/reperfusion, suggesting that blood cell Orai1 may represent a marker informing potential Th17 activity in the setting of AKI or the AKI-to-CKD transition.

scholarly journals Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 1841-1854 ◽  
Author(s):  
Jun Zhou ◽  
Jiying  Zhong ◽  
Sen  Lin ◽  
Zhenxing Huang ◽  
Hongtao Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Kidney Injury ◽  
Control Group ◽  
Kidney Fibrosis

Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

Immune Cells in Ischemic Acute Kidney Injury

2019 ◽  
Vol 20 (8) ◽  
pp. 770-776 ◽  
Author(s):  
Long Zheng ◽  
Wenjun Gao ◽  
Chao Hu ◽  
Cheng Yang ◽  
Ruiming Rong
Keyword(s):  
Acute Kidney Injury ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systemic Disease ◽  
Kidney Injury ◽  
Repair Process ◽  
Injured Kidney

Acute kidney injury (AKI) is a systemic disease characterized by acute loss of renal function and accumulation of end products of nitrogen metabolism. Ischemic AKI is the most common cause of AKI, and inflammatory responses are inevitablely involved in ischemic AKI. In the process of ischemic AKI, multiple factors are involved in activating and recruitment of immune cell to the injured kidney. These factors include DAMPs and HIFs released from the injured kidney, increased expression of adhesion molecules, the production of chemokines and cytokines, activation of complement system and TLRs as well as the permeability dysfunction of the renal vascular endothelium. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after ischemia reperfusion injury (IRI), with some of their subpopulations also participating in the repair process. Numerous studies of immune cells involved in the pathogenesis of AKI have enhanced the understanding of their possible mechanisms in AKI which might become the potential targets for the treatment of ischemic AKI. This review describes the function of the immune cells in the pathogenesis and repair of ischemic AKI and emphasizes the treatment of ischemic AKI potentially targeting them.

Upregulated miR-101 inhibits acute kidney injury–chronic kidney disease transition by regulating epithelial–mesenchymal transition

2020 ◽  
Vol 39 (12) ◽  
pp. 1628-1638 ◽  
Author(s):  
J-Y Zhao ◽  
X-L Wang ◽  
Y-C Yang ◽  
B Zhang ◽  
Y-B Wu
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Mesenchymal Transition

Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). However, the role and mechanism of microRNA (miRNA, miR) in AKI-CKD transition are elusive. In this study, a murine model of renal ischemia/reperfusion was established to investigate the repairing effect and mechanism of miR-101a-3p on renal injury. The pathological damage of renal tissue was observed by hematoxylin and eosin and Masson staining. The levels of miR-101, profibrotic cytokines, and epithelial–mesenchymal transition (EMT) markers were analyzed using Western blotting, real-time polymerase chain reaction, and/or immunofluorescence. MiR-101 overexpression caused the downregulation of α-smooth muscle actin, collagen-1, and vimentin, as well as upregulation of E-cadherin, thereby alleviating the degree of renal tissue damage. MiR-101 overexpression mitigated hypoxic HK-2 cell damage. Collagen, type X, alpha 1 and transforming growth factor β receptor 1 levels were downregulated in hypoxic cells transfected with miR-101 mimic. Our study indicates that miR-101 is an anti-EMT miRNA, which provides a novel therapeutic strategy for AKI-CKD transition.

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