Abstract MP08: New Function Of Sox6 In Renovascular Hypertension Induced Oxidative Stress And Kidney Damage Through Renin, Prorenin And The (pro)renin Receptor Expression Control.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mohammad Saleem ◽  
Pierina Barturen-Larrea ◽  
Sergey I Dikalov ◽  
Jose A Gomez
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Creatinine Clearance ◽  
Renovascular Hypertension ◽  
High Performance ◽  
Kidney Injury ◽  
Housekeeping Gene ◽  
Kidney Damage ◽  
Receptor Expression ◽  
Superoxide Production

Introduction: During renovascular hypertension induced by renal artery stenosis (RAStenosis), smooth muscle cells are recruited to produce and release renin compensating for the decrease in renal perfusion. In renovascular hypertension, renin expression increases causing a surge in angiotensin II, oxidative stress and kidney damage. Here we present a new function of the transcription factor Sox6 in kidney injury and oxidative damage during RAStenosis. Methods: We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Ren1d Cre /Sox6 fl/fl -Sox6-KO). We developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to induce RAStenosis. We measured superoxide production (pmol/mg pr) in kidney using high-performance liquid chromatography in Sox6-KO and Ren1d Cre /Sox6 wt/wt (Sox6-WT) littermates. Renin, prorenin, (pro)renin receptor (PRR) and N-GAL expressions were measured using Western blot using β-actin as housekeeping gene. Western blot band density analysis was performed using ImageJ. Kidney injury was determined by measuring creatinine clearance. Results: We found that Sox6-KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, p<0.01), and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, p<0.05) and mice are protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, p<0.01), and kidney injury measuring N-GAL expression (1.3 vs. 2.7, SEM=0.38, n=6-8, p<0.01) and creatinine clearance (2372 vs. 1341, SEM=342.3, n=4-5, p<0.05). Furthermore, we found that the levels of superoxide were significantly lower in Sox6-KO mice compared to Sox6-WT littermates (218 vs 47, SEM=50.6, N=7, P<0.01). The expression of PRR was significantly lower in Sox6-KO compared to Sox6-WT during RAStenosis (1.23 vs. 0.72, SEM=0.33, n=2-5, p<0.01). Conclusions: Our results show that Sox6 depletion in renin expressing cells inhibits the increase in renovascular hypertension and prevents the increase in renin, prorenin, PRR, and N-GAL expression as well as superoxide production, preserving creatinine clearance during RAStenosis. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.

Abstract MP02: Sox6 Ablation In Renin Expressing Cells Protects Mice Against Hypertension And Kidney Injury

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Mohammad Saleem ◽  
Pierina Barturen ◽  
Luz A Saavedra ◽  
Jose A Gomez
Keyword(s):  
Mouse Model ◽  
Renal Artery ◽  
Creatinine Clearance ◽  
Renovascular Hypertension ◽  
Colorimetric Assay ◽  
Kidney Injury ◽  
The United States ◽  
Receptor Expression ◽  
Knockout Mouse Model ◽  
Prorenin Receptor

Introduction: The Renin angiotensin aldosterone system (RAAS) is implicated in renal artery stenosis (RAS) and renovascular hypertension. RAS or renal artery occlusion is an intractable problem affecting about 6% of people over 65 and up to 40% of the people with coronary or peripheral vascular disease in the United States. Renin being the rate limiting enzyme in RAAS is considered the key driver of RAS. The mechanism of renin regulation during RAS is still elusive and warrants further investigation. Here we studied the function of the transcription factor Sox6 in the renin regulation using a new knockout mouse model during RAS. Methods: We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Sox6 KO). Using these mice, we developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to constrict right renal artery to induce RAS. Two weeks after surgery, renin, prorenin, prorenin receptor (PRR), and N-GAL expressions were measured using Western blot. Blood pressure was measured using tail-cuff method. Creatinine clearance was measured in urine using a colorimetric assay. Results: Comparing Sox6 KO with the Sox6 wild type littermates, we found that Sox6 KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, P<0.01) and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, P<0.05). Sox6 KO mice were protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, P<0.01), and kidney injury during RAS. Furthermore, we found that the levels of creatinine clearance were preserved in Sox6 KO mice compared to WT littermates (2372 vs. 1341, SEM=342.3, n=4-5, P<0.05) during RAS. The levels of the kidney injury marker N-GAL were significantly lower in KO mice compared to WT littermates (1.3 vs. 2.7, SEM=0.38, n=6-8, P<0.01). Similarly, PRR receptor expression were significantly lower in KO compared to WT (1.23 vs. 0.72, SEM=0.33, n=2-5, P<0.01) during RAS. Conclusions: Our results show that knocking out Sox6 in renin expressing cells inhibits renovascular hypertension, renin, prorenin, PRR, and N-GAL expression, and preserve creatinine clearance induced by RAS. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.

scholarly journals Recurrent insulin-induced hypoglycemia induces AngII and COX2 leading to renal (pro)renin receptor expression and oxidative stress

2017 ◽  
Vol 5 (1) ◽  
pp. 71 ◽  
Author(s):  
Wael Alanazi ◽  
Mohammad Uddin ◽  
Selim Fakhruddin ◽  
Keith Jackson
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Kidney Injury ◽  
Organ Damage ◽  
Day Surgery ◽  
Receptor Expression ◽  
Sprague Dawley ◽  
Subunit Expression ◽  
Renal Biomarker ◽  
And Oxidative Stress

Background: Recurrent insulin-induced hypoglycemia (RIIH) is an avoidable consequence in the therapeutic management of diabetes mellitus. RIIH has been implicated in causing hypertension through an increase in renal and systemic AngII production.Objective: The present study was performed to assess the hypothesis that chronic insulin treatment enhances AngII and COX2 formation which in turn increases (pro) renin receptor (PRR) expression and NADPH oxidase-mediated oxidative stress, leading to renal and cardiac injury.Methods: The present studies were conducted in Male Sprague Dawley rats treated with daily subcutaneous injections of 7u/kg insulin or saline for 14 days. On the 14th day, surgery was performed for treatment infusion (captopril 12mg/kg, NS398 0.3mg/kg or vehicle), and renal interstitial fluid sample and urine collections for biomarker measurements. At the end of the experiments, kidneys and hearts were harvested to evaluate PRR and NOX2 (NADPH oxidase subunit) expression and oxidative stress.Results: We found that RIIH enhanced AngII and COX2 activity, leading to renal PRR expression and NADPH oxidase-induced oxidative stress in the heart and kidney. 8-isoprostane was evaluated as a renal biomarker of oxidative stress, which was induced in insulin treated animals and modulated by captopril and NS398. In addition, there was a slight increase in NGAL, a urinary biomarker of acute kidney injury (AKI), in insulin treated animals when compared to control.Conclusion: These results demonstrate that RIIH induces renal PRR expression and oxidative stress through increasing AngII and COX2 in the heart and kidney, leading to end-organ damage.

scholarly journals Salvianolic Acid A Protects the Kidney against Oxidative Stress by Activating the Akt/GSK-3β/Nrf2 Signaling Pathway and Inhibiting the NF-κB Signaling Pathway in 5/6 Nephrectomized Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Hong-feng Zhang ◽  
Jia-hong Wang ◽  
Yan-li Wang ◽  
Cheng Gao ◽  
Yan-ting Gu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Signaling Pathway ◽  
Kidney Injury ◽  
Dependent Manner ◽  
Salvianolic Acid ◽  
Nrf2 Signaling Pathway ◽  
Antioxidative Effects ◽  
Dose Dependent

Salvianolic acid A (SAA) is a bioactive polyphenol extracted from Salviae miltiorrhizae Bunge, which possesses a variety of pharmacological activities. In our previous study, we have demonstrated that SAA effectively attenuates kidney injury and inflammation in an established animal model of 5/6 nephrectomized (5/6Nx) rats. However, there has been limited research regarding the antioxidative effects of SAA on chronic kidney disease (CKD). Here, we examined the antioxidative effects and underlying mechanisms of SAA in 5/6Nx rats. The rats were injected with SAA (2.5, 5, and 10 mg·kg-1·d-1, ip) for 28 days. Biochemical, flow cytometry, and Western blot analyses showed that SAA significantly increased the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and catalase (CAT) and lowered the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and NADPH oxidase 4 (NOX-4) in a dose-dependent manner in 5/6Nx rats and in H2O2-induced HK-2 cells in vitro. Moreover, SAA enhanced the activation of the protein kinase B/glycogen synthase kinase-3β/nuclear factor-erythroid-2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathway in a dose-dependent manner and subsequently increased the expression of heme oxygenase-1 (HO-1) in the kidney of 5/6Nx rats, which were consistent with those obtained in H2O2-induced HK-2 cells in vitro shown by Western blot analysis. Furthermore, SAA significantly increased the expression of intranuclear Nrf2 and HO-1 proteins compared to HK-2 cells stimulated by LPS on the one hand, which can be enhanced by QNZ to some extent; on the other hand, SAA significantly lowered the expression of p-NF-κB p65 and ICAM-1 proteins compared to HK-2 cells stimulated by H2O2, which can be abrogated by ML385 to some extent. In conclusion, our results demonstrated that SAA effectively protects the kidney against oxidative stress in 5/6Nx rats. One of the pivotal mechanisms for the protective effects of SAA on kidney injury was mainly related with its antioxidative roles by activating the Akt/GSK-3β/Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway.

scholarly journals Total Coumarins fromHydrangea paniculataProtect against Cisplatin-Induced Acute Kidney Damage in Mice by Suppressing Renal Inflammation and Apoptosis

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Zhang Sen ◽  
Ma Jie ◽  
Yang Jingzhi ◽  
Wang Dongjie ◽  
Zhang Dongming ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Southern China ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Stat3 Signaling ◽  
Inflammatory Status ◽  
Stat3 Signaling Pathway ◽  
Underlying Mechanisms

Aim.Hydrangea paniculata (HP) Sieb. is a medical herb which is widely distributed in southern China, and current study is to evaluate renal protective effect of aqueous extract of HP by cisplatin-induced acute kidney injury (AKI) in animal model and its underlying mechanisms.Materials and Methods.HP extract was prepared and the major ingredients were coumarin glycosides. AKI mouse models were established by single i.p. injection of 20 mg/kg cisplatin, and HP was orally administrated for total five times. The renal biochemical functions, pathological staining, kidney oxidative stress, and inflammatory status were measured. Apoptosis of tubular cells and infiltration of macrophages and neutrophils were also tested.Results.HP administration could improve the renal function by decreasing concentration of blood urea nitrogen (BUN) and creatinine and attenuates renal oxidative stress and tubular pathological injury and apoptosis; further research demonstrated that HP could inhibit the overproduction of proinflammatory cytokines and regulate caspase and BCL-2 family proteins. HP also reduced renal infiltration of macrophages and neutrophils, and its effect might be by downregulating phosphorylation of ERK1/2 and stat3 signaling pathway.Conclusions.This present study suggests that HP could ameliorate cisplatin induced kidney damage by antioxidation and suppressing renal inflammation and tubular cell apoptosis.

scholarly journals Prior intake of Brazil nuts attenuates renal injury induced by ischemia and reperfusion

2018 ◽  
Vol 40 (1) ◽  
pp. 10-17 ◽  
Author(s):  
Natassia Alberici Anselmo ◽  
Leticia Colombo Paskakulis ◽  
Renata Correia Garcias ◽  
Fernanda Fortuci Resende Botelho ◽  
Giovana Queda Toledo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Creatinine Clearance ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Properties ◽  
Kidney Injury ◽  
Urinary Output ◽  
Left Renal Artery ◽  
And Oxidative Stress

ABSTRACT Introduction: Ischemia-reperfusion (IR) injury results from inflammation and oxidative stress, among other factors. Because of its anti-inflammatory and antioxidant properties, the Brazil nut (BN) might attenuate IR renal injury. Objective: The aim of the present study was to investigate whether the intake of BN prevents or reduces IR kidney injury and inflammation, improving renal function and decreasing oxidative stress. Methods: Male Wistar rats were distributed into six groups (N=6/group): SHAM (control), SHAM treated with 75 or 150 mg of BN, IR, and IR treated with 75 or 150 mg of BN. The IR procedure consisted of right nephrectomy and occlusion of the left renal artery with a non-traumatic vascular clamp for 30 min. BN was given daily and individually for 7 days before surgery (SHAM or IR) and maintained until animal sacrifice (48h after surgery). We evaluated the following parameters: plasma creatinine, urea, and phosphorus; proteinuria, urinary output, and creatinine clearance; plasmatic TBARS and TEAC; kidney expression of iNOS and nitrotyrosine, and macrophage influx. Results: Pre-treatment with 75 mg of BN attenuated IR-induced renal changes, with elevation of creatinine clearance and urinary output, reducing proteinuria, urea, and plasmatic phosphorus as well as reducing kidney expression of iNOS, nitrotyrosine, and macrophage influx. Conclusion: Low intake of BN prior to IR-induced kidney injury improves renal function by inhibition of macrophage infiltration and oxidative stress.

scholarly journals Effects of Tristetraprolin on Doxorubicin (Adriamycin)-induced experimental nephrotic syndrome though inhibiting IL-13 /STAT6 signal pathway

2019 ◽  
Author(s):  
Qian Zhang ◽  
Ge Wu ◽  
Shiyuan Guo ◽  
Yong Liu ◽  
Zhangsuo Liu
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Epithelial Cell ◽  
Western Blot ◽  
Cell Line ◽  
Renal Injury ◽  
Kidney Injury ◽  
Adverse Outcomes ◽  
Epithelial Cell Line

Abstract Background: To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). Methods: DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of the animal groups under investigation were recorded daily throughout the experimental period. Histological changes were observed using Hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and ROS, MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, intracellular levels of oxidative stress were assessed using 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining. TTP and Kim-1 expression levels were measured by immunohistochemistry and western blot. The TNF-α, IL-1β and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected via western blot, respectively. CCK-8 was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. Results: DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Conclusion: Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.

scholarly journals The Kidney Injury Induced by Short-Term PM2.5 Exposure and the Prophylactic Treatment of Essential Oils in BALB/c Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yining Zhang ◽  
Qiujuan Li ◽  
Mengxiong Fang ◽  
Yanmin Ma ◽  
Na Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Essential Oils ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Ros Generation ◽  
Short Term ◽  
Ras Activation

PM2.5 is well known as a major environmental pollutant; it has been proved to be associated with kidney diseases. The kidney damage involves oxidative stress and/or inflammatory response. NOX4 is a major source of reactive oxygen species (ROS) generation in the kidney, and the excessive generation of ROS is recognized to be responsible for oxidative stress. To elucidate whether short-term PM2.5 exposure could induce kidney damage, we exposed BALB/c mice to PM2.5 intratracheally and measured the biomarkers of kidney injury (KIM-1, cystatin C), oxidative stress (MDA, SOD-1, and HO-1), and inflammatory response (NF-κB, TNF-α). Acute kidney damage and excessive oxidative stress as well as transient inflammatory response were observed after PM2.5 installation. The overexpression of some components of the angiotensin system (RAS) after PM2.5 exposure illustrated that RAS may be involved in PM2.5-induced acute kidney injury. CEOs (compound essential oils) have been widely used because of their antioxidant and anti-inflammation properties. Treatment with CEOs substantially attenuated PM2.5-induced acute kidney injury. The suppression of RAS activation was significant and earlier than the decrease of oxidative stress and inflammatory response after CEOs treatment. We hypothesized that CEOs could attenuate the acute kidney injury by suppressing the RAS activation and subsequently inhibit the oxidative stress and inflammatory response.

scholarly journals USP10 alleviates sepsis-induced acute kidney injury by regulating Sirt6-mediated Nrf2/ARE signaling pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fei Gao ◽  
Mingjiang Qian ◽  
Guoyue Liu ◽  
Wanping Ao ◽  
Dahua Dai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cell ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Renal Tubular Epithelial Cell ◽  
Renal Tubular

Abstract Background Severe sepsis, a major health problem worldwide, has become one of the leading causes of death in ICU patients. Further study on the pathogenesis and treatment of acute kidney injury (AKI) is of great significance to reduce high mortality rate of sepsis. In this study, the mechanism by which ubiquitin specific peptidase 10 (USP10) reduces sepsis-induced AKI was investigated. Ligation and perforation of cecum (CLP) was employed to establish C57BL/6 mouse models of sepsis. Hematoxylin-eosin (H&E) staining was performed to detect renal injury. The concentrations of serum creatinine (Cr), urea nitrogen (BUN) and cystatin C (Cys C) were determined using a QuantiChrom™ Urea Assay kit. RT-qPCR and western blot were conducted to assess the USP10 expression level. DHE staining was used to detect reactive oxygen species (ROS) levels. H2O2, MDA and SOD levels were assessed using corresponding colorimetric kits. Western blot was used to examine the expression levels of Bcl-2, Bax, cleaved caspase-3, Sirt6, Nrf2 and HO-1. MTT assay was used to determine cell viability, whereas TUNEL staining and flow cytometry were used to assess cell apoptosis. Results In this study, we found that USP10 was decreased in CLP-induced mouse renal tissues. We identified that USP10 alleviated renal dysfunction induced by CLP. Moreover, USP10 was found to reduce oxidative stress, and abated LPS-induced renal tubular epithelial cell injury and apoptosis. Finally, we discovered that USP10 promoted activation of the NRF2/HO-1 pathway through SIRT6 and attenuated LPS-induced renal tubular epithelial cell injury. Conclusions This study found that USP10 activates the NRF2/ARE signaling through SIRT6. USP10 alleviates sepsis-induced renal dysfunction and reduces renal tubular epithelial cell apoptosis and oxidative stress.

scholarly journals Selenium Protects against Zearalenone-Induced Oxidative Stress and Apoptosis in the Mouse Kidney by Inhibiting Endoplasmic Reticulum Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yi Zhang ◽  
Bo Hu ◽  
Mingyang Wang ◽  
Jingjing Tong ◽  
Jianwen Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Control Group ◽  
Tunel Staining ◽  
Expression Of Genes ◽  
Induced Apoptosis ◽  
And Oxidative Stress

This study assessed the molecular mechanism of selenium (Se) protecting against kidney injury induced by zearalenone (ZEA) in mice. The experimental mice were divided into 4 groups including the control group, the Se group, the ZEA group, and the Se+ZEA group; ZEA and Se were administered orally for 28 days. The changes in renal biochemical index (BUN, UA, and CRE), biochemical change of kidney damage such as BUN, UA, and CRE, and oxidative damage such as MDA, T-SOD, and GSH-Px were investigated. Pathological sections and TUNEL staining were used to analyze renal pathological changes and cell apoptosis. qRT-PCR and Western blot were employed to detect the expression of genes and proteins which were related with endoplasmic reticulum stress. The results showed that ZEA increased the concentration of BUN, UA, and CRE and the content of MDA and decreased the activities of T-SOD and GSH-Px in the mouse kidneys. However, Se reversed above changes of the biochemical and antioxidant indexes of renal injury. Moreover, the results also showed that ZEA can increase the expression of Bax, caspase-12, caspase-3, Bip, CHOP, JNK protein, and mRNA and decrease the expression of Bcl-2 protein and mRNA. But Se reversed these proteins and genes related to endoplasmic reticulum stress and apoptosis. It can be concluded that Se protected against the kidney damage induced by ZEA. Se may protect the kidney from ZEA-induced apoptosis and oxidative stress by inhibiting ERS.

Eudragit L-100 Capsules Aromatize and Quaternerize Chitosan for Insulin Nanoparticle Oral Delivery During Toxic Oxidative Stress in Rat Liver and Kidney

2020 ◽  
Vol 8 (3) ◽  
pp. 239-254 ◽  
Author(s):  
Reza Mahjub ◽  
Farzane K. Najafabadi ◽  
Narges Dehkhodaei ◽  
Nejat Kheiripour ◽  
Amir N. Ahmadabadi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oral Administration ◽  
Oral Delivery ◽  
Biochemical Parameters ◽  
Kidney Injury ◽  
Regular Insulin ◽  
Treated Group ◽  
Histopathological Change ◽  
Diabetic Rats ◽  
Liver And Kidney

Background: Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome. Objective: In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied. Methods: INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining . Results: Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups. Conclusion: Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe. Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.

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