Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy

Miguel A. Lanaspa, Takuji Ishimoto, Christina Cicerchi, Yoshifuru Tamura, Carlos A. Roncal-Jimenez, Wei Chen, Katsuyuki Tanabe, Ana Andres-Hernando, David J. Orlicky, Esteban Finol, Shinichiro Inaba, Nanxing Li, Christopher J. Rivard, Tomoki Kosugi, Laura G. Sanchez-Lozada, J. Mark Petrash, Yuri Y. Sautin, A. Ahsan Ejaz, Wataru Kitagawa, Gabriela E. GarciaDavid T. Bonthron, Aruna Asipu, Christine P. Diggle, Bernardo Rodriguez-Iturbe, Takahiko Nakagawa, Richard J. Johnson

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase - deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

Original languageEnglish
Pages (from-to)2526-2538
Number of pages13
JournalJournal of the American Society of Nephrology
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Lanaspa, M. A., Ishimoto, T., Cicerchi, C., Tamura, Y., Roncal-Jimenez, C. A., Chen, W., Tanabe, K., Andres-Hernando, A., Orlicky, D. J., Finol, E., Inaba, S., Li, N., Rivard, C. J., Kosugi, T., Sanchez-Lozada, L. G., Petrash, J. M., Sautin, Y. Y., Ejaz, A. A., Kitagawa, W., ... Johnson, R. J. (2014). Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. Journal of the American Society of Nephrology, 25(11), 2526-2538. https://doi.org/10.1681/ASN.2013080901