scholarly journals Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

2021 ◽  
Vol 22 (19) ◽  
pp. 10822
Author(s):  
Agata Winiarska ◽  
Monika Knysak ◽  
Katarzyna Nabrdalik ◽  
Janusz Gumprecht ◽  
Tomasz Stompór
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Organ Protection ◽  
In Vivo Models ◽  
Diabetic Kidney ◽  
And Oxidative Stress

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

FC 087MIR-155/SOCS1 REGULATORY LOOP INFLUENCES DIABETIC KIDNEY DISEASE BY JAK/STAT PATHWAY MODULATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ignacio Prieto ◽  
Luna Jimenez-Castilla ◽  
Iolanda Lazaro ◽  
Susana Bernal-Uribe ◽  
Laura Lopez-Sanz ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Regulatory Loop ◽  
And Oxidative Stress ◽  
Stat Pathway

Abstract Background and Aims Diabetic nephropathy is the leading cause of chronic kidney disease worldwide. Hyperglycemia in concert with cytokines activate Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and induce gene expression of many inflammatory and oxidative stress mediators, which are critical events at all stages of diabetic kidney disease. Suppressor of cytokine signaling 1 (SOCS1) is a STAT-inducible protein and a negative feedback regulator of JAK/STAT pathway. The microRNA-155 is an epigenetic modulator of SOCS1 gene by repressing its translation and, at the same time, is a transcriptional target of STAT, thus completing another regulatory loop of JAK/STAT pathway. Therefore, our aim was to explore the interplay between miR-155 and JAK/STAT/SOCS1 axis in experimental diabetic nephropathy. Method In streptozotocin-induced type 1 diabetic aged mice (wild-type and apolipoprotein E (apoE) knockout) we analyzed the kidney levels of miR-155 and markers of renal damage, inflammation and oxidative stress. In vitro, the expression of miR-155, SOCS1 and STAT1 in mesangial, tubuloepithelial and macrophage cell lines were modulated by silencing/inhibition or overexpression/mimicking experiments to further determine the JAK/STAT pathway activation and expression of downstream target genes. Results In vivo, type 1 diabetes significantly upregulated miR-155 expression in kidneys from both wild-type and apoE knockout mice (1.8- and 4.5-fold vs respective non-diabetic controls). The miR-155 levels directly correlated with parameters of renal damage (serum creatinine, albuminuria, kidney-to-body weight ratio and renal score) and the mRNA expression of chemokines (Ccl2 and Ccl5) and pro-oxidant enzymes (Nox2 and Nox4), but inversely with antioxidant genes (Sod1 and Cat). In vitro, the expression of miR-155 was increased in renal cells and macrophages exposed to hyperglycemia and/or inflammatory conditions. Overexpression of miR-155 reduced SOCS1 expression, enhanced STAT1 and STAT3 activation and pro-inflammatory cytokines and chemokines (Il6, Tnfa, Ccl2 and Cxcl10) expression. By contrast, miR-155 antagonist upregulated SOCS1 and had a protective effect on renal cells by decreasing STAT1/3 phosphorylation and pro-inflammatory gene expression. Additionally, loss- or gain-of function experiments indicate a direct implication of SOCS1 in the regulation of miR-155 expression by STAT transcription factors. Conclusion Our study indicates a pro-inflammatory role of miR-155 in diabetic kidney disease by downregulating renal expression of SOCS1. Therefore, antagonism of miR-155 may have a renoprotective effect in diabetic nephropathy through SOCS1-mediated feedback inhibition of JAK/STAT overactivation. Ongoing in vivo studies with miR-155 inhibitor in experimental diabetes will clarify its role in the development and progression of diabetic nephropathy.

scholarly journals miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mitsuo Kato ◽  
Maryam Abdollahi ◽  
Ragadeepthi Tunduguru ◽  
Walter Tsark ◽  
Zhuo Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Mitochondrial Fission ◽  
Major Complication ◽  
Body Weight Loss ◽  
Diabetic Kidney ◽  
Guide Rna ◽  
And Oxidative Stress

AbstractDiabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.

Abstract 016: Profound and Sustained Amplification of Circulating ACE2 Activity Does Not Protect Diabetic Mice from Kidney Disease

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Minghao Ye ◽  
Ahmed M Khattab ◽  
Yashpal Kanwar ◽  
Mark Osborn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Over Expression ◽  
Akita Mice

ACE2 is a monocarboxypeptidase that by converting AngII to Ang1-7 should down-regulate the renin-angiotensin system and therefore provide a means to therapeutically target diabetic kidney disease, a condition where the kidney RAS is overactive. Previous work indicated that soluble human recombinant (r)ACE2 administration for 4 weeks attenuated kidney injury in diabetic Akita mice. Whether such effect of rACE2 can be confirmed and attributed to augmented ACE2 activity is uncertain because chronic use of human rACE2 in mice induces immunogenicity and the development of antibodies that neutralize serum ACE2 activity. To examine the effect of chronic amplification of circulating ACE2 on kidney injury caused by STZ-induced diabetes and to circumvent the immunogenicity arising from xenogeneic ACE2, ACE2 of mouse origin was administered to mice using either daily i.p. injections (1 mg/kg) of mrACE2 for 4 weeks or after 20 weeks of ACE2 mini-circle (MC) (10-30ug/mouse) administration. MC provides a form of gene delivery that is resistant to gene silencing and, in addition, greatly optimizes long-term in vivo overexpression of proteins of interest. ACE2MC resulted in a profound and sustained increase in serum ACE2 activity (2.4±0.3 vs. 497±135 RFU/ul/hr, p<0.01) but kidney ACE2 activity was unchanged (17.4±1.3 vs. 19.0±0.8 RFU/ug prot/hr). mACE2-treated mice injected with STZ developed diabetes similar to sham mice injected with STZ. Systolic BP was not different between non-diabetic mice, sham STZ-mice, and STZ-mice receiving mACE2 by either i.p. mrACE2 or ACE2MC. Urinary albumin was similarly increased in sham STZ-mice and in STZ-mice receiving mACE2. Glomerular mesangial score and glomerular cellularity were both increased to a similar extent in sham STZ-mice and in STZ-mice with mACE2 administration, as compared to non-diabetic controls. In conclusion, profound and long-term augmentation of ACE2 activity confined to the circulation is not sufficient to attenuate glomerular pathology and albuminuria in STZ-induced diabetic kidney disease probably because of lack of kidney delivery of ACE2. Strategies to achieve over-expression of ACE2 at the kidney level are needed to demonstrate a beneficial effect of this enzyme on diabetic kidney disease.

scholarly journals The protective effect of klotho against contrast-associated acute kidney injury via the antioxidative effect

2019 ◽  
Vol 317 (4) ◽  
pp. F881-F889 ◽  
Author(s):  
Hyung Jung Oh ◽  
Hyewon Oh ◽  
Bo Young Nam ◽  
Je Sung You ◽  
Dong-Ryeol Ryu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Injury ◽  
Antioxidative Effect ◽  
In Vivo Experiments ◽  
Apoptotic Markers ◽  
Cytoplasmic Vacuoles ◽  
Transmission Electron ◽  
And Oxidative Stress

As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the antioxidative effect. In in vitro experiments, cells (NRK-52E) were divided into the following three groups: control, iopamidol, or iopamidol + recombinant klotho (rKL) groups. Moreover, cell viability was measured with the Cell Counting Kit-8 assay, and oxidative stress was examined with 2',7'-dichlorodihydrofluorescein diacetate fluorescence intensity. RT-PCR and Western blot analysis were performed to assess propidium iodide klotho expression, and Bax-to-Bcl-2 and apoptosis ratios were evaluated with annexin V/Hoechst 33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In our in vivo experiments, oxidative stress was evaluated with the thiobarbituric acid-reactive substance assay, and apoptosis was evaluated with the Bax-to-Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with transmission electron microscopy. In both in vitro and in vivo experiments, mRNA and protein expression of klotho significantly decreased in CA-AKI mice compared with control mice, whereas oxidative stress and apoptosis markers were significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mouse model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mouse model using transmission electron microscopy but fewer cytoplasmic vacuoles in rKL-supplemented cells. The present study shows that klotho in proximal tubular cells can protect against CA-AKI via an antioxidative effect.

scholarly journals S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Qi Li ◽  
Delma Veron ◽  
Alda Tufro
Keyword(s):  
Kidney Disease ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Diabetic Mice ◽  
Post Translational Modification ◽  
No Donor ◽  
Diabetic Kidney ◽  
Rhoa Activity

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

scholarly journals Isoquercitrin Ameliorates Cisplatin-Induced Nephrotoxicity Via the Inhibition of Apoptosis, Inflammation, and Oxidative Stress

2020 ◽  
Vol 11 ◽  
Author(s):  
Hao Wang ◽  
Weiwei Xia ◽  
Guangfeng Long ◽  
Zhiyin Pei ◽  
Yuanyuan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Cell Injury ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Epithelial Cell Line ◽  
Therapeutic Uses ◽  
And Oxidative Stress

Cisplatin is extensively used and is highly effective in clinical oncology; nevertheless, nephrotoxicity has severely limited its widespread utility. Isoquercitrin (IQC), a natural flavonoid widely found in herbage, is well known and recognized for its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the potential effects and mechanism of IQC in cisplatin-induced acute kidney diseases remain unknown. In this study, we postulated the potential effects and mechanism of IQC upon cisplatin exposure in vivo and in vitro. For the in vivo study, C57BL/6J mice were pretreated with IQC or saline (50 mg/kg/day) by gavage for 3 days before cisplatin single injection (25 mg/kg). Renal function, apoptosis, inflammation, oxidative stress and p-ERK were measured to evaluate kidney injury. In vitro, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cell line (HK2) were pretreated with or without IQC (80 μM for mPTCs and 120 μM for HK2) for 2 h and then co-administrated with cisplatin for another 24 h. Apoptosis, inflammation, ROS and p-ERK of cells were also measured. In vivo, IQC administration strikingly reduced cisplatin-induced nephrotoxicity as evidenced by the improvement in renal function (serum creatinine and blood urea nitrogen), kidney histology (PAS staining), apoptotic molecules (cleaved caspase-3, caspase-8, Bax and Bcl-2), inflammatory cytokines (IL-1β, IL-6, TNF-α, and COX-2), oxidative stress (MDA and total glutathione) and p-ERK. In line with in vivo findings, IQC markedly protected against cisplatin-induced cell injury in mPTCs and HK2 cells. Collectively, these findings demonstrated that IQC administration could significantly protect against cisplatin nephrotoxicity possibly through ameliorating apoptosis, inflammation and oxidative stress accompanied by cross talk with p-ERK. Furthermore, IQC may have potential therapeutic uses in the treatment of cisplatin-induced acute kidney injury.

scholarly journals Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dongdong Yuan ◽  
Xiaoyun Li ◽  
Chenfang Luo ◽  
Xianlong Li ◽  
Nan Cheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Cx43 Expression

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

scholarly journals Characterizing the Role of Biologically Relevant Fluid Dynamics on Silver Nanoparticle Dependent Oxidative Stress in Adherent and Suspension In Vitro Models

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 832
Author(s):  
Katherine E. Burns ◽  
Robert F. Uhrig ◽  
Maggie E. Jewett ◽  
Madison F. Bourbon ◽  
Kristen A. Krupa
Keyword(s):  
Oxidative Stress ◽  
Fluid Dynamics ◽  
In Vitro Models ◽  
Poor Correlation ◽  
Cellular Interactions ◽  
Dynamic Flow ◽  
In Vivo Models ◽  
And Oxidative Stress

Silver nanoparticles (AgNPs) are being employed in numerous consumer goods and applications; however, they are renowned for inducing negative cellular consequences including toxicity, oxidative stress, and an inflammatory response. Nanotoxicological outcomes are dependent on numerous factors, including physicochemical, biological, and environmental influences. Currently, NP safety evaluations are carried out in both cell-based in vitro and animal in vivo models, with poor correlation between these mechanisms. These discrepancies highlight the need for enhanced exposure environments, which retain the advantages of in vitro models but incorporate critical in vivo influences, such as fluid dynamics. This study characterized the effects of dynamic flow on AgNP behavior, cellular interactions, and oxidative stress within both adherent alveolar (A549) and suspension monocyte (U937) models. This study determined that the presence of physiologically relevant flow resulted in substantial modifications to AgNP cellular interactions and subsequent oxidative stress, as assessed via reactive oxygen species (ROS), glutathione levels, p53, NFκB, and secretion of pro-inflammatory cytokines. Within the adherent model, dynamic flow reduced AgNP deposition and oxidative stress markers by roughly 20%. However, due to increased frequency of contact, the suspension U937 cells were associated with higher NP interactions and intracellular stress under fluid flow exposure conditions. For example, the increased AgNP association resulted in a 50% increase in intracellular ROS and p53 levels. This work highlights the potential of modified in vitro systems to improve analysis of AgNP dosimetry and safety evaluations, including oxidative stress assessments.

scholarly journals Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Zhang Yifan ◽  
Ning Benxiang ◽  
Xu Zheng ◽  
Xu Luwei ◽  
Zhou Liuhua ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Injury ◽  
Oxidative Stress Markers ◽  
Stress Injury ◽  
Stress Markers ◽  
Oxidative Stress Injury ◽  
Calcium Crystals ◽  
And Oxidative Stress

Objective. To investigate the role of inflammatory reactions and oxidative stress injury in the mechanisms of ceftriaxone calcium crystal-induced acute kidney injury (AKI) both in vivo and in vitro. Methods. Male Sprague Dawley rats were randomly divided into five groups of ten each according to different concentrations of ceftriaxone and calcium. Based on the levels of serum creatinine (Scr) and blood urea nitrogen (BUN), the AKI group was chosen for the subsequent experiments. Kidney histological examination and immunohistochemistry were performed. The expression of NLRP3 and IL-1β protein and the concentrations of oxidative stress markers such as ROS, MDA, and H2O2 in kidney tissues were estimated. In parallel, HK-2 human renal proximal tubule cells were exposed to ceftriaxone calcium crystals. The mRNA expression levels of NLRP3 and IL-1β and the concentrations of oxidative stress markers were evaluated. Finally, cell viability and rat survival were also assessed. Results. The results showed that significantly increased Scr and BUN levels, consistent with morphological changes and kidney stones, were found in the rats that received the highest concentration of ceftriaxone (1000 mg/kg) combined with calcium (800 mg/kg). The activation of the NLRP3 inflammasome axis and the marked elevation of MDA, H2O2, and ROS levels were observed both in vivo and in vitro. High expression of Nrf2, HO-1, and NQO1 was also documented. In addition, cell apoptosis and rat mortality were promoted by ceftriaxone calcium crystals. Conclusions. Notably, we found that ceftriaxone-induced urolithiasis was associated with a high risk of AKI and NLRP3-mediated inflammasome and oxidative stress injury were of major importance in the pathogenesis.

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