FC 042IRF8 IN CDC1 IS PROTECTIVE IN POST-ISCHEMIC ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Li Na ◽  
Stefanie Steiger ◽  
Lingyan Fei ◽  
Chenyu Li ◽  
Chongxu Shi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kidney Disease ◽  
Kidney Function ◽  
Ischemia Reperfusion ◽  
Expression Patterns ◽  
Kidney Injury ◽  
Mononuclear Phagocytes ◽  
Moderate Increase ◽  
Acute Kidney Disease

Abstract Background and Aims Post-ischemic acute tubular necrosis is a common cause of acute kidney disease (AKD) and subsequent chronic kidney disease. In AKD, mononuclear phagocytes (MPCs) including conventional dendritic cells (cDCs) are present during the different phases of kidney injury, repair and regeneration. The contribution of cDCs to AKD is still poorly understood. Hence, we hypothesized that transcription factor interferon regulatory factor 8 (IRF8)-specific cDCs regulate the immune response in AKD. Method AKD was induced by unilateral ischemia reperfusion injury in IRF8-deficient Clec9a-specific DCs (IRF8fl/fl Clec9acre/cre or cre/wt) and wild type C57BL/6 mice. Immune phenotyping of leukocytes in kidney and spleen and mRNA expression profiling were performed, as well as kidney function evaluated. For in vitro studies, IRF8 small interfering RNA transfection technology on bone marrow-derived DCs was used. Results In the healthy kidney and lymphoid organ (e.g., spleen and kidney draining lymph node), we identified four MPC subsets according to the diverse expression patterns of CD11b and CD11c. Of which, IRF8 was specifically expressed in the CD11blow CD11chigh R4 subset (containing mainly cDC1). During AKD, IRF8 deficiency in cDCs reduced the number of MHCII+ DCs accumulating among tubulointerstium space without affecting cDC2 or CD64+ DCs, while completely abolished cDC1 in post-ischemic kidney (See Figure). This was accompanied with a decrease in the surface expression of chemokine receptor CCR7 and CCR9, reduction in the number of kidney CD4- CD8+ T cells and Tregs, but a moderate increase in TH1-related and pro-inflammatory cytokines and infiltrating neutrophils in the kidney of mice with IRF8-deficient cDCs. This was in line with reduced kidney function, marked by aggravated GFR loss, elevated plasma BUN level, kidney atrophy, pathological tubular injury and living proximal tubule loss. In vitro, bone marrow-derived IRF8-deficient DCs showed an impaired ability to repair “artificially injured” tubular epithelial cells (TECs), accompanied with less phagocytosis capacity and maturation capacity under necrotic TECs soup or histone stimulation. Conclusion Our data show that the restricted depletion of IRF8 in cDCs reduces the number of infiltrating kidney cDC1, which drives tissue inflammation and damage, and ultimately aggravates post-ischemic AKD. Thus, cDC1s are having a protective role in AKD.

Abstract 161: Identification of Genetic Variants Associated with Kidney Injury That Leads to Increased Blood Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ashlyn C Harmon ◽  
Ashley C Johnson ◽  
Santosh Atanur ◽  
Klio Maratou ◽  
Tim Aitman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Bone Marrow ◽  
Immune Response ◽  
Renal Function ◽  
Kidney Disease ◽  
Kidney Function ◽  
Genetic Variants ◽  
Kidney Injury ◽  
Chromosome 11 ◽  
Genomic Locus

Hypertension, diabetes and obesity, along with genetic predisposition, contribute to the growing number of chronic kidney disease patients. Our novel congenic model [S.SHR(11)] was developed through genetic modification of the Dahl salt-sensitive (S) rat, a model of hypertension related renal disease. The S.SHR(11) strain exhibits accelerated kidney injury compared to the already highly susceptible S rat. On either a low or high-salt diet, the S.SHR(11) model predominately exhibited more tubulointerstitial fibrosis compared to the S rat (17.1±1.29% vs. 12.9±1.22%). Increased α-SMA and macrophage infiltration was also observed. The S and S.SHR(11) had similar blood pressure (week 12), despite an early reduction in renal function in the S.SHR(11); however at an advanced age the S.SHR(11) demonstrated significantly higher blood pressure than the S (215±6.6 mm Hg vs. 183±5.9, respectively). This suggests that increased kidney injury is driving the development of hypertension later in life. Since these two animal models are identical with exception of chromosome 11, the causative genetic variants contributing to decreased renal function must reside within this region. The Dahl S and SHR genomes have been sequenced; this data provides a catalog of all the genetic variants between the two models. The 95% confidence interval of the genomic locus contains 28 non-synonymous SNP, with 15 of these SNP occurring within only three genes: Retnlg , Trat1 and Myh15. Two of these genes, Retnlg and Trat1, are known to play a role in immune response leading to our hypothesis that genetic variants in these genes alter protein function and lead to an increased immune response. Bone marrow transplant studies have been initiated to test our hypothesis and preliminary data shows that S rats who receive S.SHR(11) bone marrow have kidney function measurements similar to the S.SHR(11). The sequencing information has also lead to the development of nine new, more refined congenic strains. Through functional analysis of these new congenic animals, identification of the causative genetic variations will be expedited. In summary, we are employing a model of accelerated kidney disease to identify genes or genetic variants responsible for reduced kidney function and hypertension.

scholarly journals Human amniotic epithelial cells ameliorate kidney damage in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cell (hAEC) is an ideal stem cell source. Increasing evidence suggests that exosomes may act as critical cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs and their derived exosomes (hAECs-EXO) in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms. Methods The hAECs were primary cultured, and hAECs-EXO were isolated and characterized. An ischemic-reperfusion injury-induced AKI (IRI-AKI) mouse model was established to mimic clinical ischemic kidney injury with different disease severity. Mouse blood creatinine level was used to assess renal function, and kidney specimens were processed to detect cell proliferation, apoptosis, and capillary density. Macrophage infiltration was analyzed by flow cytometry. hAEC-derived exosomes (hAECs-EXO) were used to treat hypoxia-reoxygenation (H/R) injured HK-2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAECs-EXO were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results We found that systematically administered hAECs could improve mortality and renal function in IRI-AKI mice, decrease the number of apoptotic cells, prevent peritubular capillary loss, and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their source cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production, and immunomodulation. These findings demonstrated that paracrine of exosomes might be the key mechanism of hAECs in alleviating renal ischemia reperfusion injury. Conclusions We reported hAECs could improve survival and ameliorate renal injury in mice with IRI-AKI. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs are at least partially, through paracrine pathways. hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells, for patients with AKI.

scholarly journals Human amniotic epithelial cells improve kidney repair in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background: Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and very limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cells (hAECs) are ideal alternative stem cell source for regenerative medicine. Increasing evidence suggests that hAEC-derived exosomes (hAECs-EXO) may act as novel cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms.Methods: The hAECs were primary cultured and hAECs-EXO were isolated and characterized. An ischemic renal injury mouse model was established to mimic different severity of the kidney injury. Mouse blood creatinine level was used to assess renal function and kidney specimens were processed to detect cell proliferation, apoptosis and angiogenesis. Immune cells infiltration was analyzed by flow cytometry. hAECs-EXO was used to treat hypoxia-reoxygenation (H/R) injured HK2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAEC exosomes were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results: We found that systematically administered hAECs could improve mortality and renal function in IRI mice; decrease the number of apoptotic cells; promote peritubular capillary regeneration and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their parent cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production and immunomodulation. These findings demonstrated that paracrine of exosomes might be a key mechanism by hAECs mediating kidney functional recovery in AKI.Conclusions: We first reported hAECs could improve mortality and renal repair in mice with ischemia-reperfusion injury. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs at least partially, through paracrine pathways. The renoprotective effects of hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells for patients with AKI.

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.

MO067PHASE-SPECIFIC IRF4 AND IRF8 REGULATION/EXPRESSION OF MONONUCLEAR PHAGOCYTES DURING ISCHEMIC ACUTE KIDNEY INJURY/DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Na Li ◽  
Stefanie Steiger ◽  
Chenyu Li ◽  
Zhihua Zheng ◽  
Hans-Joachim Anders ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Kidney Disease ◽  
Hypoxic Condition ◽  
Mononuclear Phagocytes ◽  
Rt Pcr ◽  
Renal Lymph ◽  
Resident Macrophage ◽  
Repair Phase

Abstract Background Ischemic acute tubular necrosis is a common cause of acute kidney disease (AKD) and subsequent chronic kidney disease (CKD). The different phases of AKD involve a greater functional diversity of mononuclear phagocytes (MPCs) including resident and infiltrating macrophages and conventional dendritic cells (cDCs). In addition, hematopoietic transcription factors such as IRF4 and IRF8 play an important role in immune cell maturation and polarization that contribute to tissue inflammation and remodeling. However, their role on MPCs polarization and function during AKD are not well understood. Hence, we hypothesized that the dynamically altered MPC subsets contribute to the progression of AKD, accompanied with varied expression of IRF4 and IRF8. Methods AKD was induced by transient unilateral renal pedicle clamping in C57BL/6N mice. After 1, 3, and 7 days kidneys, renal lymph nodes and spleens were collected. Flow cytometry was performed to identify different MPC subsets. GFR was measured and mRNA expression of inflammatory, anti-inflammatory transcription factors determined via RT-PCR. For in vitro experiments, bone marrow-derived macrophages and cDCs, tubular epithelial cells (TECs), renal and splenic resident CD11b+ immune cells isolated from naïve mice were stimulated with LPS or cultured under hypoxic condition for 3 and 10 hours. Bone marrow-derived monocytes were differentiated into macrophages or cDCs, and stimulated with LPS for 3 and 10 hours. After stimulation, cells were harvested for mRNA analysis via RT-PCR. Results We identified four renal phenotypically distinct MPC subsets with diverse expression patterns of CD11b/CD11c during the different phases of post-ischemic AKD. During the early (day 1) and late injury phase (day 3), the number of infiltrating CD11bhiCD11clow R2 and CD11bhiCD11chi R3 macrophage-like subsets increased, along with a significant GFR decline compared with sham-operated mice (see Figure). During the repair phase (day 7), the number of CD11blowCD11clow R1 (resident macrophage-like MPCs) and CD11blowCD11chi R4 (infiltrating cDC-like MPCs) subsets significantly increased (see Figure). Both resident macrophage-like (R1) and cDC-like (R4) MPCs significantly upregulated the expression of IRF8, whereas cDCs-like (R4) MPCs were also positive for IRF4 during the repair phase. This pattern of MPCs was consistent in spleen and renal lymph node. In vitro stimulation of renal and splenic CD11b+ cells from naïve mice with LPS or under hypoxic condition induced a significant upregulation of IRF4 and IRF8 compared to untreated cells. This was also observed in bone marrow-derived macrophages and cDCs but not in TECs. Conclusions Our data indicate that infiltrating macrophage-like and cDC-like MPCs appear in high numbers during the early and late injury phase. Furthermore, both resident macrophage-like and cDC-like MPCs are predominately present during the late injury and recovery phase in AKD with altered IRF4 and IRF8 expression pattern. Further studies are needed to unravel a potential role of IRF4 and IRF8 during the progression of AKD and CKD by e.g. using fate mapping approaches.

Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Fadia A Kamal ◽  
Joshua G Travers ◽  
Allison E Schafer ◽  
Qing Ma ◽  
Prasad Devarajan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
G Protein ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Direct Role

Background: Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation. Objective: CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model. Methods and results: We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation. Conclusion: Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.

scholarly journals P0564INCIDENCE AND PROGNOSIS OF ACUTE KIDNEY INJURY VERSUS ACUTE KIDNEY DISEASE AMONG 71,041 INPATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Chenyu Li ◽  
Long Zhao ◽  
Lingyu Xu ◽  
Chen Guan ◽  
Zhibo Zhao ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Impairment ◽  
Kidney Function ◽  
De Novo ◽  
Kidney Injury ◽  
Acute Kidney Disease ◽  
Long Term Mortality

Abstract Background and Aims The current diagnostic criteria for acute kidney injury (AKI) predict the need for dialysis and early mortality, but are less useful to predict long-term outcomes. Acute kidney disease (AKD) defines patients with AKI or subacute loss of kidney function lasting for more than 7 days, which should predict better subsequent chronic kidney disease (CKD). The aim of this study was to investigate the risk factors and prognosis of AKD and to compare different types of acute/subacute renal impairment among Chinese inpatients. Method From a cohort of 450,000 patients consecutive admitted from June 1, 2012, to March 31, 2018 to five district hospitals, complete data were available from 71,041 inpatients. AKI and AKD were diagnosed based on the Acute Disease Quality Initiative Criteria 2017. Based on this diagnostic criterion of AKI and AKD, patients were classified as having (1) AKI Recover, if Scr back to baseline value within 7 days (renal impairment duration of less than 7 days or rapid recovery within 7 days), and (2) AKD with AKI, if a condition in which stage 1 or greater AKI was present ≥ 7 days after an AKI initiating event (continuous AKI progressing to AKD), (3) AKD without AKI, if Scr levels increased slowly but lasted more than 7 days (subacute AKD without meeting the AKI criterion). Results Of 71,041 inpatients, 16,098 (22.66%) patients developed AKI or AKD. 5,895 (8.30%) AKI patients recovered within 7 days (AKI Recover), 5,623 (7.91%) were followed by AKD and 4,580 (6.44%) patients developed AKD without AKI. Thus, AKI and AKD are frequent complications in Chinese inpatients (Fig 1). Compared to AKI recover or AKD without AKI, patients with AKI followed by AKD had higher hospital mortality (16.59% vs. 3.82% vs. 2.12%, P<0.05) and more de novo CKD (8.95% vs. 7.29% vs. 5.48%, P<0.05). Mortality was proportional to stages of AKI and AKD (P for trend <0.05), while AKI followed by AKD was associated with a higher risk of long-term mortality (hazard ratio (HR) 4.51, 4.32-4.71, P<0.05) as compared to AKD without AKI (HR 2.25, 2.13-2.39, P<0.05) and AKI Recover (HR 1.18, 1.09-1.26, P<0.05). The AKI criterion yielded a higher risk for overall survival and a lower risk for de novo CKD than the AKD criterion, indicating that both criteria imply persistent kidney damage but that a rapid decline in excretory kidney function implies higher mortality risks while a persistent decline may rather result in de novo CKD (Fig 2). Meanwhile, these associations between different kidney injury criteria and outcomes had good generalizability and were constant across different genders, surgeries, and comorbidities (Fig 2). The AKD criterion was robustly associated with overall survival (area under the receiver operating characteristic curve (AUROC) 0.71) and de novo CKD (AUROC 0.71), while AKI criterion showed a relatively lower ability to fitting risk of overall survival (AUROC 0.65, P<0.05) and CKD (AUROC 0.63, P<0.05). Moreover, combining AKI and AKD was strongly associated with long-term mortality (AUROC 0.725) and de novo CKD (AUROC 0.72) compared to each single criterion of AKI or AKD (Fig 3). Conclusion (1) Adding AKD as a definition for renal failure lasting >7 days up to 90 days is of clinical importance in addition to the existing definitions for AKI and CKD. (2) These findings suggest research activities and clinical practice should also focus on AKD, which is far more accurate to predict subsequent de novo CKD.

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 Role of TRPA1 in Tissue Damage and Kidney Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3415
Author(s):  
Chung-Kuan Wu ◽  
Ji-Fan Lin ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Kidney Disease ◽  
Tissue Damage ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cell Types ◽  
Renal Tubular

TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.

scholarly journals cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7

2021 ◽  
Author(s):  
Lilin Li ◽  
Jeonghwan Lee ◽  
Ara Cho ◽  
Jin Hyuk Kim ◽  
Wonmin Ju ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Smad Pathway ◽  
Agonistic Antibody ◽  
Kidney Fibrosis ◽  
Tgf Β1

We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-β1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory marker (MCP-1, TNF-α, and IL-1β) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-β1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-β1/Smad pathway.

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