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
. 2013 Aug;28(8):2038-45.
doi: 10.1093/ndt/gft022. Epub 2013 Mar 19.

Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy

Mohammad A Aminzadeh  1 , Susanne B Nicholas, Keith C Norris, Nosratola D Vaziri
Affiliations

Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy

Mohammad A Aminzadeh et al. Nephrol Dial Transplant. 2013 Aug.

Abstract

Background: Tubulo-interstitial nephropathy (TIN) is a common cause of chronic kidney disease (CKD). Consumption of an adenine-containing diet causes the accumulation of 2,8-dihydroxyadenine in the renal tubules triggering intense chronic TIN and progressive CKD in rats. CKD in this model is associated with, and largely driven by, oxidative stress and inflammation. Oxidative stress and inflammation in rats with spontaneous focal segmental glomerulosclerosis and rats with CKD induced by 5/6 nephrectomy are associated with an impaired activation of nuclear factor-erythroid-2-related factor 2 (Nrf2) which is the master regulator of genes encoding many antioxidant and detoxifying enzymes. The effect of TIN on the Nrf2 pathway and its key target genes is unknown and was investigated here.

Methods: Sprague-Dawley rats were randomized to control and adenine-treated (rat chow-containing 0.7% adenine for 2 weeks) groups and followed up for 4 weeks.

Results: The adenine-treated animals exhibited marked azotemia, impaired urinary concentrating capacity, intense tubular and glomerular damage, interstitial inflammation and fibrosis. This was associated with an increased expression of NAD(P)H oxidase, cyclooxygenase-2 and 12-lipoxygenase, and activation of NF-κB, the master regulator of pro-inflammatory cytokines and chemokines. Oxidative stress and inflammation in the kidneys of adenine-treated animals was accompanied by an impaired activation of Nrf2 and down-regulation of its target gene products including, catalase, heme oxygenase-1 and glutamate-cysteine ligase.

Conclusions: Chronic TIN is associated with impaired Nrf2 activity which contributes to the pathogenesis of oxidative stress and inflammation and amplifies their damaging effects on the kidney.

Keywords: CKD progression; antioxidants; chronic kidney disease; reactive oxygen species.

PubMed Disclaimer

Figures

FIGURE 1:
FIGURE 1:
Box plots of plasma concentration of oxidized glutathione (GSSG) (left panel) and the oxidized-to-reduced (GSH) glutathione ratio (right panel) in rats with adenine-induced TIN (TIN) and control (CTL) rats; n = 6 in each group. **P < 0.01.
FIGURE 2:
FIGURE 2:
Representative photomicrographs of periodic acid schiff (PAS)-stained kidney sections from a rat with adenine-induced TIN (TIN) and a control (CTL) rat. The kidney in the TIN animals exhibited significant tubulo-interstitial injury marked by tubular dilation, heavy inflammatory cell infiltration and fibrosis. Magnification ×200.
FIGURE 3:
FIGURE 3:
Representative western blots and group data depicting protein abundance of the NAD(P)H oxidase subunits (NOX-4, Rac1, p67phox and gp91phox) in the renal tissues of rats with adenine-induced TIN (TIN) and control (CTL) rats n = 6 in each group. **P < 0.01.
FIGURE 4:
FIGURE 4:
Representative western blots and group data depicting protein abundance of cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LO), phospho-IκB and nuclear content of p65 active subunit of NF-κB in the renal tissues of rats with adenine-induced TIN (TIN) and control (CTL) rats n = 6 in each group. **P < 0.01.
FIGURE 5:
FIGURE 5:
Representative western blots and group data depicting nuclear translocation of Nrf2 and protein abundances of its repressor, Keap1, and its downstream gene products, catalase, heme oxygenase-1 (HO-1) and catalytic (GCLC) subunit of glutamate-cysteine ligase in the renal tissues of the adenine-treated (TIN) and control (CTL) rats; n = 6 in each group.**P < 0.01
See this image and copyright information in PMC

References

    1. Fujihara CK, Antunes GR, Mattar AL, et al. Chronic inhibition of nuclear factor-kappaB attenuates renal injury in the 5/6 renal ablation model. Am J Physiol Renal Physiol. 2007;292:F92–F99. doi:10.1152/ajprenal.00184.2006. - DOI - PubMed
    1. Manning RD, Jr, Tian N, Meng S. Oxidative stress and antioxidant treatment in hypertension and the associated renal damage. Am J Nephrol. 2005;25:311–317. doi:10.1159/000086411. - DOI - PubMed
    1. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006;116:288–296. doi:10.1172/JCI27699. - DOI - PMC - PubMed
    1. Vaziri ND, Oveisi F, Ding Y. Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int. 1998;53:1748–1754. doi:10.1046/j.1523-1755.1998.00947.x. - DOI - PubMed
    1. Li W, Khor TO, Xu C, et al. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76:1485–1489. doi:10.1016/j.bcp.2008.07.017. - DOI - PMC - PubMed

Publication types

MeSH terms