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      Long-Term Administration of Angiotensin (1–7) to db/db Mice Reduces Oxidative Stress Damage in the Kidneys and Prevents Renal Dysfunction

      1 , , 1 , 2

      Oxidative Medicine and Cellular Longevity


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          The goal of this study was to evaluate the effects of long-term (16 weeks) administration of angiotensin (1–7) [A(1–7)] on kidney function in db/db mice and to identify the protective mechanisms of this therapy.


          db/db mice and heterozygous controls were treated with A(1–7) or vehicle daily, subcutaneously for up to 16 weeks. Kidney injury was assessed by measuring blood flow in renal arteries, plasma creatinine levels, and proteinuria. Effects of treatment on oxidative stress were evaluated by histological staining and gene expression.


          16 weeks of daily administration of A(1–7) to a mouse model of severe type 2 diabetes ( db/db) prevented the progression of kidney damage. Treatment with A(1–7) improved blood flow in the renal arteries, as well as decreased plasma creatinine levels and proteinuria in diabetic mice. Reduction of oxidative stress was identified as one of the mechanisms of the renoprotective action of A(1–7). Treatment prevented formation of nitrotyrosine residues, a marker of oxidative stress damage. A(1–7) also reduced the expression of two enzymes involved in formation of nitrotyrosine, namely, eNOS and NOX-4. A(1–7) regulated the phosphorylation pattern of eNOS to enhance production of NO in diabetic animals, possibly through the Akt pathway. However, these elevated levels of NO did not result in increased nitrosylation, possibly due to reduced NOX-4 levels.


          Long-term administration of A(1–7) improved kidney function and reduced oxidative stress damage in db/db mice.

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          Most cited references 33

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          Role of reactive oxygen species in cell signalling pathways.

          Reactive oxygen species (ROS) were originally thought to only be released by phagocytic cells during their role in host defence. It is now clear that ROS have a cell signalling role in many biological systems, both in animals and in plants. ROS induce programmed cell death or necrosis, induce or suppress the expression of many genes, and activate cell signalling cascades, such as those involving mitogen-activated protein kinases.
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            Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects.

             Rafael Radi (2013)
            In proteins, the nitration of tyrosine residues to 3-nitro-tyrosine represents an oxidative post-translational modification that disrupts nitric oxide ((•)NO) signaling and skews metabolism towards pro-oxidant processes. Indeed, excess levels of reactive oxygen species in the presence of (•)NO or (•)NO-derived metabolites lead to the formation of nitrating species such as peroxynitrite. Thus, protein 3-nitrotyrosine has been established as a biomarker of cell, tissue, and systemic "nitroxidative stress". Moreover, tyrosine nitration modifies key properties of the amino acid: phenol group pK(a), redox potential, hydrophobicity, and volume. Thus, the incorporation of a nitro group (-NO(2)) into protein tyrosines can lead to profound structural and functional changes, some of which contribute to altered cell and tissue homeostasis. In this Account, I describe our current efforts to define (1) biologically-relevant mechanisms of protein tyrosine nitration and (2) how this modification can cause changes in protein structure and function at the molecular level. First, I underscore the relevance of protein tyrosine nitration via free-radical-mediated reactions (in both peroxynitrite-dependent and -independent pathways) involving a tyrosyl radical intermediate (Tyr(•)). This feature of the nitration process is critical because Tyr(•) can follow various fates, including the formation of 3-nitrotyrosine. Fast kinetic techniques, electron paramagnetic resonance (EPR) studies, bioanalytical methods, and kinetic simulations have all assisted in characterizing and fingerprinting the reactions of tyrosine with peroxynitrite and one-electron oxidants and its further evolution to 3-nitrotyrosine. Recent findings show that nitration of tyrosines in proteins associated with biomembranes is linked to the lipid peroxidation process via a connecting reaction that involves the one-electron oxidation of tyrosine by lipid peroxyl radicals (LOO(•)). Second, immunochemical and proteomic-based studies indicate that protein tyrosine nitration is a selective process in vitro and in vivo, preferentially directed to a subset of proteins, and within those proteins, typically one or two tyrosine residues are site-specifically modified. The nature and site(s) of formation of the proximal oxidizing or nitrating species, the physicochemical characteristics of the local microenvironment, and the structural features of the protein account for part of this selectivity. How this relatively subtle chemical modification in one tyrosine residue can sometimes cause dramatic changes in protein activity has remained elusive. Herein, I analyze recent structural biology data of two pure and homogenously nitrated mitochondrial proteins (i.e., cytochrome c and manganese superoxide dismutase, MnSOD) to illustrate regioselectivity and structural effects of tyrosine nitration and subsequent impact in protein loss- or even gain-of-function.
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              Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney.

              Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. We investigated the role of the NAD(P)H oxidase Nox4 in generation of reactive oxygen species (ROS), hypertrophy, and fibronectin expression in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides for Nox4 were administered for 2 weeks with an osmotic minipump 72 h after streptozotocin treatment. Nox4 protein expression was increased in diabetic kidney cortex compared with non-diabetic controls and was down-regulated in AS-treated animals. AS oligonucleotides inhibited NADPH-dependent ROS generation in renal cortical and glomerular homogenates. ROS generation by intact isolated glomeruli from diabetic animals was increased compared with glomeruli isolated from AS-treated animals. AS treatment reduced whole kidney and glomerular hypertrophy. Moreover, the increased expression of fibronectin protein was markedly reduced in renal cortex including glomeruli of AS-treated diabetic rats. Akt/protein kinase B and ERK1/2, two protein kinases critical for cell growth and hypertrophy, were activated in diabetes, and AS treatment almost abolished their activation. In cultured mesangial cells, high glucose increased NADPH oxidase activity and fibronectin expression, effects that were prevented in cells transfected with AS oligonucleotides. These data establish a role for Nox4 as the major source of ROS in the kidneys during early stages of diabetes and establish that Nox4-derived ROS mediate renal hypertrophy and increased fibronectin expression.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                23 October 2018
                : 2018
                1School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA
                2School of Medicine, Center for Innovation in Brain Sciences, University of Arizona, 1230 N. Cherry Ave., Tucson, AZ 85721, USA
                Author notes

                Guest Editor: Mohamed M. Abdel-Daim

                Copyright © 2018 Anna Malgorzata Papinska and Kathleen Elizabeth Rodgers.

                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.

                Funded by: National Institutes of Health
                Award ID: 5R01HL082722-02
                Research Article

                Molecular medicine


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