Possible role of mitochondrial injury in Caulis Aristolochia manshuriensis-induced chronic aristolochic acid nephropathy.

Abstract

CONTEXT:

The proximal tubular epithelial cells (PTECs) are the primary target of aristolochic acids and especially vulnerable to mitochondrial injury from insults of toxic xenobiotics.

OBJECTIVES:

This study aimed to investigate the possible role of mitochondrial injury in Caulis Aristolochia manshuriensis (CAM)-induced aristolochic acid nephropathy (AAN).

MATERIALS AND METHODS:

Male Sprague-Dawley rats were gavaged with CAM extract every other week for 1, 4, 8 and 12 weeks, respectively.

RESULTS:

The rats in the model group showed chronic AAN as evidenced by worsening kidney function evaluated by blood urea nitrogen, creatinine and proteinuria levels, and severe tubulointerstitial injury marked by massive tubular atrophy and interstitial fibrosis in kidney tissues. Moreover, overt apoptosis and impaired regeneration of PTECs were observed in AAN rats. Furthermore, the study revealed that mitochondria in PTECs were fragmented into small, punctuate suborganelles in AAN rats. Two mitochondrial respiratory chain proteins, mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit І (COX-І) and nuclear DNA-encoded nicotinamide adenine dinucleotide dehydrogenase (ubiquinone)-1β subcomplex 8 (NDUFβ8), were both down-regulated after one week of CAM treatment. However, with AAN progression, NDUFβ8 level restored, while COX-І level maintained low. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), master regulator of mitochondrial biogenesis, was significantly down-regulated at week 4 and week 8, but significantly up-regulated at week 12. In addition, mtDNA copy number reduced markedly along with AAN progression.

DISCUSSION AND CONCLUSION:

A rat model of chronic AAN was successfully reproduced by gavage with CAM extract. Dynamic changes of mitochondrial injury induced by CAM might contribute to the AAN progression.

• Authors: Xinhui Liu, Juan Wu, Juan Wang, Jinjin Fan, Xiaoran Feng, Xueqing Yu, Xiao Yang
• Journal: Drug and chemical toxicology (Drug Chem Toxicol) Vol. 40 Issue 1 Pg. 115-124 (Jan 2017) ISSN: 1525-6014 [Electronic] United States
• PMID: 27250112 (Publication Type: Journal Article)

Chemical References

• Aristolochic Acids
• Biomarkers
• Drugs, Chinese Herbal
• aristolochic acid I

Topics

• Animals
• Apoptosis (drug effects)
• Aristolochia (chemistry)
• Aristolochic Acids (isolation & purification, toxicity)
• Biomarkers (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal (isolation & purification, toxicity)
• Kidney Cortex (drug effects, ultrastructure)
• Kidney Function Tests
• Kidney Tubules, Proximal (drug effects, ultrastructure)
• Male
• Mitochondria (drug effects, ultrastructure)
• Nephritis, Interstitial (blood, chemically induced, pathology, urine)
• Rats, Sprague-Dawley