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      Nephroprotective Effect of Adropinin Against Streptozotocin-Induced Diabetic Nephropathy in Rats: Inflammatory Mechanism and YAP/TAZ Factor

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          Abstract

          Background

          Diabetic Nephropathy remains a major cause of morbidity and mortality in patients suffering from renal dysfunction. This study accessed the nephroprotective role of Adropinin against streptozotocin (STZ) induced diabetic nephropathy in rats and scrutinizes the possible mechanism of action.

          Methods

          STZ (45 mg/kg) dose was used for inducing diabetic nephropathy (DN) and rats were divided into different groups and received the dose-dependent treatment of Adropinin. Blood glucose level, body weight, tissue weight, antioxidant, renal, hepatic parameters, and cytokines were determined. At the end of the experimental study, renal histopathology was performed.

          Results

          Adropinin significantly (P<0.001) boosted plasma insulin levels and reduced the blood glucose level. Adropinin considerably increased body weight and reduced kidney weight and kidney hypertrophy. Adropinin significantly (P<0.001) reduced urine outflow, microalbumin, total protein, blood urea nitrogen (BUN), uric acid and increased the creatinine, creatinine clearance. Adropinin significantly (P<0.001) reduced the indole sulfate level in the serum, kidney and reduced in the urine. Adropinin significantly (P<0.001) reduced the total cholesterol, triglyceride, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and increased the level of high-density lipoprotein (HDL). Adropinin significantly (P<0.001) increased the level of antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and reduced the level of malonaldehyde (MDA), 8-hydroxy-2ʹ -deoxyguanosine (8-OHdG). Adropinin significantly (P<0.001) reduced the level of interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor beta (TGF-β) and increased the level of interleukin-10 (IL-10), respectively. Adropinin treatment showed improvement in renal histopathology.

          Conclusion

          We can say that Adropinin showed the nephroprotective effect against the STZ-induced diabetic nephropathy rats via inflammatory and antioxidant pathway.

          Most cited references43

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          The role of inflammatory cytokines in diabetic nephropathy.

          Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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            Oxidative stress and metabolic syndrome.

            Metabolic syndrome is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Metabolic syndrome is often characterized by oxidative stress, a condition in which an imbalance results between the production and inactivation of reactive oxygen species. Reactive oxygen species can best be described as double-edged swords; while they play an essential role in multiple physiological systems, under conditions of oxidative stress, they contribute to cellular dysfunction. Oxidative stress is thought to play a major role in the pathogenesis of a variety of human diseases, including atherosclerosis, diabetes, hypertension, aging, Alzheimer's disease, kidney disease and cancer. The purpose of this review is to discuss the role of oxidative stress in metabolic syndrome and its major clinical manifestations (namely coronary artery disease, hypertension and diabetes). It will also highlight the effects of lifestyle modification in ameliorating oxidative stress in metabolic syndrome. Discussion will be limited to human data.
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              Inflammation in Diabetic Nephropathy

              Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                16 February 2021
                2021
                : 15
                : 589-600
                Affiliations
                [1 ]Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University , Jinan, Shandong Province, 250012, People’s Republic of China
                Author notes
                Correspondence: Xiaoyan Xiao Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University , No. 107 Wenhuaxi Road, Jinan, Shandong Province, 250012, People’s Republic of China Email xiaoyanxiao2007@sina.com
                Article
                294009
                10.2147/DDDT.S294009
                7896734
                ec4b999a-c311-4473-a157-aa02177ac9f6
                © 2021 Guo et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 09 December 2020
                : 26 January 2021
                Page count
                Figures: 10, References: 43, Pages: 12
                Funding
                Funded by: Key R & D project of Shandong Province (Public welfare tackling of key scientific and technical problems);
                The current research was funded by {Key R & D project of Shandong Province (Public welfare tackling of key scientific and technical problems), 2019GSF108111 role and mechanism of Yap / TAZ in diabetic nephropathy}.
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                nephropathy,diabetes mellitus,adropinin,renal,antioxidant,inflammation

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