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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2014 ; 25
(11
): 2526-38
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Endogenous fructose production and fructokinase activation mediate renal injury
in diabetic nephropathy
#MMPMID24876114
Lanaspa MA
; Ishimoto T
; Cicerchi C
; Tamura Y
; Roncal-Jimenez CA
; Chen W
; Tanabe K
; Andres-Hernando A
; Orlicky DJ
; Finol E
; Inaba S
; Li N
; Rivard CJ
; Kosugi T
; Sanchez-Lozada LG
; Petrash JM
; Sautin YY
; Ejaz AA
; Kitagawa W
; Garcia GE
; Bonthron DT
; Asipu A
; Diggle CP
; Rodriguez-Iturbe B
; Nakagawa T
; Johnson RJ
J Am Soc Nephrol
2014[Nov]; 25
(11
): 2526-38
PMID24876114
show ga
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.
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