Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats.
Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2'-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state.
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Shinichiro
S
Asakawa
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Shigeru
0000-0002-6868-0626
S
Shibata
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Chikayuki
C
Morimoto
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan; Support for Community Medicine Endowed Chair, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
Takeshi
T
Shiraishi
Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie 511-0406, Japan.
Takashi
T
Nakamura
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Yoshifuru
Y
Tamura
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan; Support for Community Medicine Endowed Chair, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
Takanori
T
Kumagai
Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Makoto
M
Hosoyamada
Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Shunya
0000-0002-0480-4212
S
Uchida
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000150:complications*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D033461:Hyperuricemia / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D018384:Oxidative Stress / Q000187:drug effects; D010094:Oxonic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D014503:Urate Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014527:Uric Acid / Q000097:blood; D014968:Xanthine Dehydrogenase / Q000378:metabolism
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000199:Actins; D003497:Cyclic N-Oxides; D003849:Deoxyguanosine; D003893:Desmin; D010094:Oxonic Acid; D013113:Spin Labels; D014503:Urate Oxidase; D014527:Uric Acid; D014968:Xanthine Dehydrogenase; C498862:Acta2 protein, rat; C001803:tempol