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      Attenuation of Diabetic Nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats with a Combination of Chinese Herbs (Tangshen Formula)

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          Abstract

          Diabetic nephropathy is one of the most significant microvascular complications in patients with type 2 diabetics. The concise mechanism of diabetic nephropathy is unknown and there is no successful treatment. The objective of study was to investigate effects of Chinese herbs (Tangshen Formula) on diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats and LETO rats were divided into four groups: LETO control, OLETF diabetics, OLETF diabetics treated with Tangshen Formula, and OLETF diabetics treated with Monopril. Body weight, blood glucose, and 24 h urinary proteins were measured once every four weeks. Blood samples and kidney tissues were obtained for analyses of total cholesterol, triglyceride, whole blood viscosity, plasma viscosity, and pathohistological examination at 36 and 56 weeksrespectively. Untreated OLETF rats displayed diabetic nephropathy over the study period. Treatment of OLETF rats with Tangshen Formula attenuated the increases in blood glucose, body weight, 24 h urinary protein content, serum total cholesterol, whole blood viscosity and plasma viscosity at certain time. Treatment with Tangshen Formula also reduced glomerulosclerotic index and interstitial fibrotic index seen in OLETF rats. In conclusion, Tangshen Formula could attenuate the development of diabetic nephropathy in OLETF rat diabetic model.

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          Diabetic nephropathy: diagnosis, prevention, and treatment.

          Jorge Gross, Mirela de Azevedo, Sandra P Silveiro … (2005)
          Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c 1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.
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            Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain.

            K Kawano, T Hirashima, S Mori … (1992)
            A spontaneously diabetic rat with polyuria, polydipsia, and mild obesity was discovered in 1984 in an outbred colony of Long-Evans rats, which had been purchased from Charles River Canada (St. Constant, Quebec, Canada) in 1982. A strain of rats developed from this rat by selective breeding has since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan) and named OLETF. The characteristic features of OLETF rats are 1) late onset of hyperglycemia (after 18 wk of age); 2) a chronic course of disease; 3) mild obesity; 4) inheritance by males; 5) hyperplastic foci of pancreatic islets; and 6) renal complication (nodular lesions). Histologically, the changes of pancreatic islets can be classified into three stages: 1) an early stage (6-20 wk of age) of cellular infiltration and degeneration; 2) a hyperplastic stage (20-40 wk of age); and 3) a final stage (at > 40 wk of age). These clinical and pathological features of disease in OLETF rats resemble those of human NIDDM.
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              From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy.

              Gunter Wolf, Sheldon Chen, F Ziyadeh (2005)
              Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Evid Based Complement Alternat Med
                Journal ID (publisher-id): ECAM
                Title: Evidence-based Complementary and Alternative Medicine : eCAM
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1741-427X
                ISSN (Electronic): 1741-4288
                Publication date (Print): 2011
                Publication date (Electronic): 17 January 2011
                Publication date PMC-release: 17 January 2011
                Volume: 2011
                Electronic Location Identifier: 613737
                Affiliations
                1Department of Pharmacology, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Hepingli, Beijing 100029, China
                2Faculty of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada R3E 0T5
                3Faculty of Medicine, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada R3E 0T5
                4Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Hai Yun Cang, Dongcheng District, Beijing 100700, China
                Author notes
                Article
                DOI: 10.1155/2011/613737
                PMC ID: 3026976
                PubMed ID: 21274280
                SO-VID: a53a1e23-40a0-4d59-b347-54ebbe3cae9a
                Copyright © Copyright © 2011 Haojun Zhang et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 21 July 2010
                Date revision received : 22 November 2010
                Date accepted : 13 December 2010
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Complementary & Alternative medicine
                Data availability:
                ScienceOpen disciplines: Complementary & Alternative medicine

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