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      Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice

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          Abstract

          Aims/hypothesis

          The aim of the study was to investigate the effects of genetic deficiency of aldose reductase in mice on the development of key endpoints of diabetic nephropathy.

          Methods

          A line of Ar (also known as Akr1b3)-knockout (KO) mice, a line of Ar-bitransgenic mice and control C57BL/6 mice were used in the study. The KO and bitransgenic mice were deficient for Ar in the renal glomeruli and all other tissues, with the exception of, in the bitransgenic mice, a human AR cDNA knockin-transgene that directed collecting-tubule epithelial-cell-specific AR expression. Diabetes was induced in 8-week-old male mice with streptozotocin. Mice were further maintained for 17 weeks then killed. A number of serum and urinary variables were determined for these 25-week-old mice. Periodic acid–Schiff staining, western blots, immunohistochemistry and protein kinase C (PKC) activity assays were performed for histological analyses, and to determine the levels of collagen IV and TGF-β1 and PKC activities in renal cortical tissues.

          Results

          Diabetes-induced extracellular matrix accumulation and collagen IV overproduction were completely prevented in diabetic Ar-KO and bitransgenic mice. Ar deficiency also completely or partially prevented diabetes-induced activation of renal cortical PKC, TGF-β1 and glomerular hypertrophy. Loss of Ar results in a 43% reduction in urine albumin excretion in the diabetic Ar-KO mice and a 48% reduction in the diabetic bitransgenic mice ( p < 0.01).

          Conclusions/interpretation

          Genetic deficiency of Ar significantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo. Robust and specific inhibition of aldose reductase might be an effective strategy for the prevention and treatment of diabetic nephropathy.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-011-2045-4) contains supplementary material, which is available to authorised users.

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          Most cited references46

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          Identification and characterization of a novel human aldose reductase-like gene.

          Roger S. Chung, Frank Fan, D Cao (1998)
          We have identified a novel human protein that is highly homologous to aldose reductase (AR). This protein, which we called ARL-1, consists of 316 amino acids, the same size as AR, and its amino acid sequence is 71% identical to that of AR. It is more closely related to the AR-like proteins such as mouse vas deferens protein, fibroblast growth factor-regulated protein, and Chinese hamster ovary reductase, with 81, 82, and 83%, respectively, of its amino acid sequence identical to the amino acid sequence of these proteins. The cDNA of ARL-1 was expressed in Escherichia coli to obtain recombinant protein for characterization of its enzymatic activities. For comparison, the cDNA of human AR was also expressed in E. coli and analyzed in parallel. These two enzymes differ in their pH optima and salt requirement, but they act on a similar spectrum of substrates. Similar to AR, ARL-1 can efficiently reduce aliphatic and aromatic aldehydes, and it is less active on hexoses. While AR mRNA is found in most tissues studied, ARL-1 is primarily expressed in the small intestines and in the colon, with a low level of its mRNA in the liver. The ability of ARL-1 to reduce various aldehydes and the locations of expression of this gene suggest that it may be responsible for detoxification of reactive aldehydes in the digested food before the nutrients are passed on to other organs. Interestingly, ARL-1 and AR are overexpressed in some liver cancers, but it is not clear if they contribute to the pathogenesis of this disease.
          Article 0 comments Cited 71 times – based on 0 reviews     Review now
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            Oxidative stress in diabetic nephropathy.

            N. Kashihara, Y. Haruna, V K Kondeti … (2010)
            Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macro-vascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes.
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              The role of protein kinase C activation in diabetic nephropathy.

              H. Noh, G.L. King (2007)
              Diabetic nephropathy is the leading cause of end-stage renal disease worldwide and an independent risk factor for all-cause and cardiovascular mortalities in diabetic patients. New insights into the molecular mechanisms that underlie the development and progression of microvascular complications of diabetes including nephropathy are emerging rapidly from experimental and clinical studies. Chronic hyperglycemia is a major initiator of diabetic microvascular complications. Activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway, enhanced polyol pathway, increased oxidative stress, and overproduction of advanced glycation end products have all been proposed as potential cellular mechanisms by which hyperglycemia induces diabetic vascular complications. The DAG-PKC pathway contributes to vascular function in many ways such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix synthesis/turnover, cell growth, angiogenesis, cytokine activation, and leukocyte adhesion. We will briefly review the current knowledge base regarding the pathogenic role for the activation of DAG-PKC pathway in diabetic nephropathy and other microvascular complications of diabetes. The results from animal studies and key clinical studies investigating specific effects of the PKC isoforms on the renal and other vascular tissues to induce diabetic complications are also reviewed.
              Article 0 comments Cited 53 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : jyqy2008@gmail.com
                Journal
                Journal ID (nlm-ta): Diabetologia
                Title: Diabetologia
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0012-186X
                ISSN (Electronic): 1432-0428
                Publication date (Electronic): 27 January 2011
                Publication date PMC-release: 27 January 2011
                Publication date (Print): May 2011
                Volume: 54
                Issue: 5
                Pages: 1242-1251
                Affiliations
                [1 ]Ministry of Education Key Laboratory for Cell Biology and Tumor Cell Engineering and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen, 361005 People’s Republic of China
                [2 ]Fujian Provincial Transgenic Core, Xiamen University Laboratory Animal Centre, Xiamen, People’s Republic of China
                [3 ]School of Nursing, The Third Military Medical University, Chongqing, People’s Republic of China
                [4 ]Division of Life Sciences, Graduate School in Shenzhen, Tsinghua University, The University Town, Shenzhen, People’s Republic of China
                [5 ]Oates Biomedical Consulting, Gales Ferry, CT USA
                Article
                Publisher ID: 2045
                DOI: 10.1007/s00125-011-2045-4
                PMC ID: 3071933
                PubMed ID: 21267539
                SO-VID: ca7ee688-935e-440b-a881-49e768466c6d
                Copyright © © The Author(s) 2011
                History
                Date received : 9 September 2010
                Date accepted : 10 December 2010
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2011

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: collagen iv,oxidative stress,aldose reductase,diabetic nephropathy,polyol pathway,pkc,tgf-β1,urinary albumin
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: collagen iv, oxidative stress, aldose reductase, diabetic nephropathy, polyol pathway, pkc, tgf-β1, urinary albumin

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