Skip to main page content
U.S. flag

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 19;20(1):61.
doi: 10.1186/1423-0127-20-61.

Depletion of the cellular antioxidant system contributes to tenofovir disoproxil fumarate - induced mitochondrial damage and increased oxido-nitrosative stress in the kidney

Premila Abraham  1 , Hemalatha Ramamoorthy, Bina Isaac
Affiliations

Depletion of the cellular antioxidant system contributes to tenofovir disoproxil fumarate - induced mitochondrial damage and increased oxido-nitrosative stress in the kidney

Premila Abraham et al. J Biomed Sci. .

Abstract

Background: Nephrotoxicity is a dose limiting side effect of tenofovir, a reverse transcriptase inhibitor that is used for the treatment of HIV infection. The mechanism of tenofovir nephrotoxicity is not clear. Tenofovir is specifically toxic to the proximal convoluted tubules and proximal tubular mitochondria are the targets of tenofovir cytotoxicity. Damaged mitochondria are major sources of reactive oxygen species and cellular damage is reported to occur after the antioxidants are depleted. The purpose of the study is to investigate the alterations in cellular antioxidant system in tenofovir induced renal damage using a rat model.

Results: Chronic tenofovir administration to adult Wistar rats resulted in proximal tubular damage (as evidenced by light microscopy), proximal tubular dysfunction (as shown by Fanconi syndrome and tubular proteinuria), and extensive proximal tubular mitochondrial injury (as revealed by electron microscopy). A 50% increase in protein carbonyl content was observed in the kidneys of TDF treated rats as compared with the control. Reduced glutathione was decreased by 50%. The activity of superoxide dismutase was decreased by 57%, glutathione peroxidase by 45%, and glutathione reductase by 150% as compared with control. Carbonic Anhydrase activity was decreased by 45% in the TDF treated rat kidneys as compared with control. Succinate dehydrogenase activity, an indicator of mitochondrial activity was decreased by 29% in the TDF treated rat kidneys as compared with controls, suggesting mitochondrial dysfunction.

Conclusion: Tenofovir- induced mitochondrial damage and increased oxidative stress in the rat kidneys may be due to depletion of the antioxidant system particularly, the glutathione dependent system and MnSOD.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(a) Body weight and (b) kidney weight of control rats and TDF treated rats. Significant reduction in kidney weights between control rats and TDF treated rats. Values represent mean ± S.D., n = 6. * P < 0.05 vs. control.
Figure 2
Figure 2
Representative light micrographs of rat kidney. (A) Renal cortex of a control rat-shows normal architecture [H& E X 200]. (B) Renal medulla of a control rat shows normal architecture [H & E, X 200]. (C) Renal cortex of a TDF treated rat. The proximal convoluted tubules were distorted and their lining epithelium was destroyed (white arrow, H & E, X 200). Some glomeruli were shrunken (black arrow). (D) Renal medulla of a TDF treated rat–There was mild destruction of the lining epithelium of the loops of Henle and the convoluted tubules (black arrow) H & E, X 200.
Figure 3
Figure 3
Representative electron micrographs of control kidney and TDF treated kidney. Control kidneys A &B. (A) Normal Kidney tubules (original magnification × 22000). (B) Normal mitochondrial structure (black arrow) in the renal tubules of control rats (original magnification × 22000) .C- F. Representative electron micrographs of TDF treated rat kidney. (C) Vacuoles seen in the cytoplasm of the kidney tubule (black arrow) Less number of lysosomes (white arrow) (D) Swollen mitochondria (M) black arrow(original magnification × 22 000) (E). Disruption of mitochondrial cristae (black arrow) in the renal tubules of TDF treated rats (F) Amorphous deposits in the mitochondrial matrix (white arrow)x 22,000.
Figure 4
Figure 4
Urine protein separation by SDS-PAGE electrophoresis. The urinary protein pattern in the TDF treated rats revealed in addition to band corresponding to albumin, multiple protein bands corresponding to molecular weights less than 55,000 dalton (especially β-2-microglobulin, suggesting complete tubular proteinuria.
Figure 5
Figure 5
Nitrate content in the kidney of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group,*p < 0.05 compared with controls.
Figure 6
Figure 6
Immunostaining for nitrotyrosine (NT). Representative nitrotyrosine staining in the kidneys of rats .In the control rat nitrotyrosine staining was minimal. In TDF treated rat kidney cortex, both proximal convoluted tubule (PCT) and distal convoluted tubules (DCT) stained strongly for NT. The glomerulus (G) showed mild staining for NT. In the medulla, loop of Henle and collecting tubules (CoT) stained for NT (X40).
Figure 7
Figure 7
Protein carbonyl content in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group,*p < 0.05 compared with controls.
Figure 8
Figure 8
TBARS levels in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 rats in each group.
Figure 9
Figure 9
Reduced glutathione levels in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group , * p < 0.05 compared with controls.
Figure 10
Figure 10
Superoxide dismutase activity in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group, ** p < 0.01 compared with controls.
Figure 11
Figure 11
Glutathione Peroxidase activity in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group .** p < 0.005 compared with controls.
Figure 12
Figure 12
Glutathione Reductase activity in the kidneys of control and TDF treated rats. Data represent mean ± SD, n = 6 in each group. ** p <0.005 compared with controls.
Figure 13
Figure 13
Carbonic anhydrase activity in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group, ** p < 0.01 compared with controls.
Figure 14
Figure 14
Succinate dehydrogenase activity in the kidneys of control rats and TDF treated rats. Data represent mean ± SD, n = 6 in each group,* p < 0.05 compared with controls.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis. 2003;37:944–950. doi: 10.1086/378068. - DOI - PubMed
    1. US Food and Drug Administration. FDA report: background package for NDA 21-356: VIREAD (tenofovir disoxoproxil fumarate) 2001. Available at: http://www.fda.gov/cder/approval/v.htm.
    1. Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-Associated Kidney Toxicity in HIV-Infected Patients: A Review of the Evidence. Am J Kidney Dis. 2011;57:773–780. doi: 10.1053/j.ajkd.2011.01.022. - DOI - PubMed
    1. Coca S, Perazella MA. Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci. 2002;324:342–344. doi: 10.1097/00000441-200212000-00011. - DOI - PubMed
    1. Rodriguez-Novoa S, Alvarez E, Labarga P, Soriano V. Renal toxicity associated with tenofovir use. Expert Opin Drug Saf. 2010;9:545–559. doi: 10.1517/14740331003627458. - DOI - PubMed

Publication types

MeSH terms