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      Effect of Bilastine on Diabetic Nephropathy in DBA2/J Mice

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          Abstract

          Diabetic nephropathy is an unmet therapeutic need, and the search for new therapeutic strategies is warranted. Previous data point to histamine H 1 receptor as a possible target for glomerular dysfunction associated with long term hyperglycaemia. Therefore, this study investigated the effects of the H 1 receptor antagonist bilastine on renal morphology and function in a murine model of streptozotocin-induced diabetes. Diabetes was induced in DBA2/J male mice and, from diabetes onset (glycaemia ≥200 mg/dL), mice received bilastine (1–30 mg/kg/day) by oral gavage for 14 consecutive weeks. At the end of the experimental protocol, diabetic mice showed polyuria (+195.5%), increase in Albumin-to-Creatine Ratio (ACR, +284.7%), and a significant drop in creatinine clearance ( p < 0.05). Bilastine prevented ACR increase and restored creatinine clearance in a dose-dependent manner, suggesting a positive effect on glomerular filtration. The ultrastructural analysis showed a preserved junctional integrity. Preservation of the basal nephrin, P-cadherin, and synaptopodin expression could explain this effect. In conclusion, the H 1 receptor could contribute to the glomerular damage occurring in diabetic nephropathy. Bilastine preserved the glomerular junctional integrity, leading to the hypothesis of anti-H 1 antihistamines as a possible add-on therapy for diabetic nephropathy.

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          Most cited references37

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          The Global Epidemiology of Diabetes and Kidney Disease

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            Cardiovascular complications of diabetic kidney disease.

            Diabetic nephropathy is the most common cause of CKD and represents a large and ominous public health problem. Patients with diabetic kidney disease have exceptionally high rates of cardiovascular morbidity and mortality. In fact, the excess mortality among patients with diabetes appears to be largely limited to the subgroup with kidney disease and explained by their high burden of cardiovascular disease. The mechanisms underlying the strong association between diabetic kidney disease and various forms of cardiovascular disease are poorly understood. Traditional risk factors for cardiovascular disease, although prevalent among those with diabetes, do not fully account for the heightened risk observed. Despite their susceptibility to cardiovascular disease, patients with CKD are less likely to receive appropriate risk factor modification than the general population. Moreover, because patients with CKD have commonly been excluded from major cardiovascular trials, the evidence for potential treatments remains limited. The mainstays of treatment for diabetic kidney disease currently include blockade of the renin-angiotensin-aldosterone system and control of hypertension, hyperglycemia, and dyslipidemia. Increased awareness of the vulnerability of this patient population and more timely interventions are likely to improve outcomes while large evidence gaps are filled with newer studies.
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              Mouse models of diabetic nephropathy.

              Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder. A consensus statement of the Animals Models of Diabetic Complications Consortium sets forth guidelines and standards for measuring renal function and structural parameters necessary for validating murine models of diabetic nephropathy. Two murine models exploiting endothelial nitric oxide synthase (eNOS) deficiency as a major susceptibility factor for development of diabetic nephropathy are among the very few options for studying features of advanced diabetic nephropathy. Akita and OVE26 mice with mutations that result in Type I diabetes are also useful models of diabetic nephropathy. The recently described BTBR ob/ob (leptin deficient) mouse with Type II diabetes demonstrates key features of early podocyte loss and mesangiolysis characteristic of human diabetic nephropathy. While there are many murine models of mesangial matrix expansion in the setting of diabetes, few progress to develop advanced diabetic lesions. Mice with eNOS deficiency, OVE26 mice, and the recently described BTBR ob/ob mouse currently appear to be the best murine models of advanced disease. A model that allows testing of interventions that modulate podocyte loss and regeneration, such as the BTBR ob/ob mouse, may be of particular benefit in developing therapeutics for diabetic nephropathy.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                24 May 2019
                May 2019
                : 20
                : 10
                : 2554
                Affiliations
                [1 ]Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; robertaverta94@ 123456gmail.com (R.V.); maura.gurrieri@ 123456live.it (M.G.); sara.borga@ 123456edu.unito.it (S.B.); monica.argenziano@ 123456unito.it (M.A.); corrado.ghe@ 123456unito.it (C.G.); roberta.cavalli@ 123456unito.it (R.C.); elisa.benetti@ 123456unito.it (E.B.); gianluca.miglio@ 123456unito.it (G.M.)
                [2 ]Department of Scienze Mediche, University of Turin, C.So Dogliotti 14, 10126 Turin, Italy; cristina.grange@ 123456unito.it
                [3 ]Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; patrizia.nardini@ 123456unifi.it
                [4 ]Department of Biotechnology and Health Sciences, Molecular Biotechnology Center University of Turin, Via Nizza 52, 10125 Turin, Italy; benedetta.bussolati@ 123456unito.it
                Author notes
                [* ]Correspondence: alessandro.pini@ 123456unifi.it (A.P.); ariannacarolina.rosa@ 123456unito.it (A.C.R.); Tel: +39-0552758155 (A.P.); +39-0116707152 (A.C.R.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-6960-5476
                https://orcid.org/0000-0002-3663-5134
                https://orcid.org/0000-0002-6139-9241
                Article
                ijms-20-02554
                10.3390/ijms20102554
                6566437
                31137660
                bc42e8c4-6169-4825-9f32-f05fa50adab8
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 April 2019
                : 21 May 2019
                Categories
                Article

                Molecular biology
                histamine,histamine h1 receptor,kidney,diabetes,slit diaphragm
                Molecular biology
                histamine, histamine h1 receptor, kidney, diabetes, slit diaphragm

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