Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Oct 20;25(12):657-684.
doi: 10.1089/ars.2016.6664. Epub 2016 Apr 1.

Diabetes and Kidney Disease: Role of Oxidative Stress

Jay C Jha  1 , Claudine Banal  1 , Bryna S M Chow  1 , Mark E Cooper  1   2 , Karin Jandeleit-Dahm  1   2
Affiliations
Review

Diabetes and Kidney Disease: Role of Oxidative Stress

Jay C Jha et al. Antioxid Redox Signal. .

Abstract

Intrarenal oxidative stress plays a critical role in the initiation and progression of diabetic kidney disease (DKD). Enhanced oxidative stress results from overproduction of reactive oxygen species (ROS) in the context of concomitant, insufficient antioxidant pathways. Renal ROS production in diabetes is predominantly mediated by various NADPH oxidases (NOXs), but a defective antioxidant system as well as mitochondrial dysfunction may also contribute. Recent Advances: Effective agents targeting the source of ROS generation hold the promise to rescue the kidney from oxidative damage and prevent subsequent progression of DKD. Critical Issues and Future Directions: In the present review, we summarize and critically analyze molecular and cellular mechanisms that have been demonstrated to be involved in NOX-induced renal injury in diabetes, with particular focus on the role of increased glomerular injury, the development of albuminuria, and tubulointerstitial fibrosis, as well as mitochondrial dysfunction. Furthermore, novel agents targeting NOX isoforms are discussed. Antioxid. Redox Signal. 25, 657-684.

Keywords: NADPH-oxidases; albuminuria; diabetic nephropathy; reactive oxygen species.

PubMed Disclaimer

Figures

<b>FIG. 1.</b>
FIG. 1.
Involvement of resident renal cells in pathogenesis of DKD. DKD, diabetic kidney disease. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 2.</b>
FIG. 2.
Overview of mediators involved in the pathogenesis of DKD. AGEs, advanced glycation end products; Akt/PKB, serine–threonine kinase; ECM, extracellular matrix; eGFR, estimated glomerular filtration rate; EMT, epithelial–mesenchymal transition; ERK1/2, extracellular signal-related kinases 1 and 2; ESRD, end-stage renal disease; GBM, glomerular basement membrane; MCP-1, monocyte chemotactic protein-1; NF-κB, nuclear factor-kappa B; p38 MAPK, p38 mitogen-activated protein kinase; PAI-1, plasminogen activator inhibitor-1; PKB, protein kinase B; PKC-α, protein kinase C-α; PKC-β, protein kinase C-β; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; VEGF, vascular endothelial growth factor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 3.</b>
FIG. 3.
Classical components of NOX catalytic subunits, NOX1, NOX2 (gp91phox), NOX4, and NOX5, and their regulatory subunits (p47phox, p67phox, p40phlox, NoxO1, NoxA1, Rac1/2, and Rap 1A) along with sources of ROS generated endogenously by renal cells and key metabolic pathways for these NOX family enzymes. CAT, catalase; Gpx, glutathione peroxidase; H2O2, hydrogen peroxide; HOCl, hypochlorous acid; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOX, NADPH oxidase; NOXA1, NOX activator 1; NOXO1, Nox organizer 1; O2•−, superoxide anion radical; •OH, hydroxyl radical; ONOO−, peroxynitrite; Poldip2, polymerase (DNA-directed) delta interacting protein 2; Rac, Ras-related C3 botulinum toxin substrate; SOD, superoxide dismutase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 4.</b>
FIG. 4.
Key mediators of glomerular cell injury in diabetes. The three key renal cell types that make up the glomeruli include the podocytes, mesangial cells, and endothelial cells. As shown, several possible mechanisms can lead to pathological changes implicated in DKD. ROS generation by NOX initiates and mediates the signaling cascades leading to cellular injury. See text for detail. ADAM17, ADAM metallopeptidase domain 17; AMPK, 5′ AMP-activated protein kinase; AngII, angiotensin II; eNOS, endothelial nitric oxide synthase; HG, high glucose; mTORC1, mammalian target of rapamycin complex 1; TRPC6, transient receptor potential cation channel, subfamily C, member 6. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 5.</b>
FIG. 5.
NOX4 and NOX5-mediated glomerular injury and albuminuria in diabetes. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 6.</b>
FIG. 6.
Key mediators of tubulointerstitial fibrosis in diabetes. α-SMA, alpha-smooth muscle actin; Ecad, epithelial cadherin; ROCK, Rho-associated protein kinase; SMAD 3, SMAD family member 3. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 7.</b>
FIG. 7.
Agents targeting NOXs in DKD. ALA, α-lipoic acid; ALD, aldosterone; CO-Q, coenzyme Q; Keap1, Kelch-like ECH-associated protein 1; Nrf2, NFE2-related factor 2; TGF-βR1, transforming growth factor receptor 1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 8.</b>
FIG. 8.
Factors associated with mitochondrial dysfunction and ROS generation in DKD. Under hyperglycemic states, more glucose is oxidized, which pushes more NADPH and FADH2 into the electron transport chain and causes excess leakage of electrons forming superoxide. Acetyl CoA, acetyl coenzyme A; ATP, adenosine triphosphate; ETC, electron transport chain; FAD, flavin adenine dinucleotide; mtDNA, mitochondrial DNA; TCA, tricarboxylic acid cycle. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
None
See this image and copyright information in PMC

References

    1. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, and Iida M. Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 109: 227–233, 2004 - PubMed
    1. Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, and Sumimoto H. Phosphorylation of p47phox directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation. Proc Natl Acad Sci U S A 100: 4474–4479, 2003 - PMC - PubMed
    1. Ago T, Kuroda J, Pain J, Fu C, Li H, and Sadoshima J. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 106: 1253–1264, 2010 - PMC - PubMed
    1. Akbar S, Bellary S, and Griffiths HR. Dietary antioxidant interventions in type 2 diabetes patients: a meta-analysis. Br J Diabetes Vasc Dis 11: 62–68, 2011
    1. Anvari E, Wikstrom P, Walum E, and Welsh N. The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice. Free Radic Res 49: 1308–1318, 2015 - PubMed

Publication types

MeSH terms

LinkOut - more resources