Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

• Published in: Laboratory investigation 2011-02, Vol.91 (2), p.190-202
• Main Authors: Satoh, Minoru, Fujimoto, Sohachi, Horike, Hideyuki, Ozeki, Masahito, Nagasu, Hajime, Tomita, Naruya, Sasaki, Tamaki, Kashihara, Naoki
• Format: Article
• Language: English
• Subjects: 631/443/272; 631/443/592/16; 631/443/7; 631/80/642/333; 8-Hydroxy-2'-Deoxyguanosine; Aging - physiology; angiogenesis; Animals; Biological and medical sciences; Biotechnology; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; hypoxia-inducible factor-1; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - physiopathology; Laboratory Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Methacrylates - pharmacology; Microscopy, Electron; mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Neovascularization, Physiologic - physiology; Oligonucleotide Array Sequence Analysis; Pathology; Rats; Rats, Wistar; reactive oxygen species; research-article; Reverse Transcriptase Polymerase Chain Reaction; Thiazoles - pharmacology; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2010.175

Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2′-deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.