Aging-associated renal disease in mice is fructokinase dependent

Carlos A. Roncal-Jimenez, Takuji Ishimoto, Miguel A. Lanaspa, Tamara Milagres, Ana Andres Hernando, Thomas Jensen, Makoto Miyazaki, Tomohito Doke, Takahiro Hayasaki, Takahiko Nakagawa, Shoichi Marumaya, David A. Long, Gabriela E. Garcia, Masanari Kuwabara, Laura G. Sánchez-Lozada, Duk Hee Kang, Richard J. Johnson

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

Original languageEnglish
Pages (from-to)F722-F730
JournalAmerican Journal of Physiology - Renal Physiology
Volume311
Issue number4
DOIs
StatePublished - 2016

Keywords

  • Aging
  • Chronic kidney disease
  • Fructose

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