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Fructokinase activity mediates dehydration-induced renal injury.

Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, Cicerchi C, Inaba S, Le M, Miyazaki M, Glaser J, Correa-Rotter R, González MA, Aragón A, Wesseling C, Sánchez-Lozada LG, Johnson RJ - Kidney Int. (2013)

Bottom Line: Both groups received the same total hydration in 24 h.This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels.These studies provide a potential mechanism for Mesoamerican nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.

ABSTRACT
The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

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Related in: MedlinePlus

Dehydration causes renal dysfunction. (a) Urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine (Cr) ratio. (b) Serum creatinine (measured by high-performance liquid chromatography (HPLC)). Data represent analysis of variance (ANOVA) (Bonferroni post test) *P<0.05. CON, control; KHK-KO, fructokinase knockout; WAN, water at night; WAT, water all time.
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fig3: Dehydration causes renal dysfunction. (a) Urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine (Cr) ratio. (b) Serum creatinine (measured by high-performance liquid chromatography (HPLC)). Data represent analysis of variance (ANOVA) (Bonferroni post test) *P<0.05. CON, control; KHK-KO, fructokinase knockout; WAN, water at night; WAT, water all time.

Mentions: As shown in Figure 2 the WT mice that were dehydrated during the day without water (the WAN group) constituted the group that showed evidence for an increase in aldose reductase activity, as noted by an increase in renal sorbitol and fructose levels. This was also the only group that showed evidence of renal injury, as noted by an increase in urinary neutrophil gelatinase-associated lipocalin (Figure 3a), serum creatinine (Figure 3b), and evidence of proximal tubular injury by renal histology (Figure 4), and with a loss of proximal tubular brush border based on staining for angiotensin-converting enzyme using computer image analysis (Figure 5). Injury was present in both proximal tubules in the renal cortex and in the outer stripe. The injury was not due to rhabdomyolysis, as serum creatine phosphokinase levels at the time of killing were normal in all mice regardless of group (creatine phosphokinase levels <10 ng/ml). Consistent with the known effects of fructose to stimulate the chemokine monocyte chemotactic protein-1 (MCP-1) in proximal tubular cells,10 we also found both an increase in renal cortical MCP-1 levels (Figure 6a) and an increase in infiltrating macrophages in the WAN group compared with the other groups of WT mice (Figure 6b) as we can see in the F4/80 stain (Figure 7). An increase in interstitial fibrosis (collagen III staining) was also observed in the WT WAN group (Figures 8 and 9).


Fructokinase activity mediates dehydration-induced renal injury.

Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, Cicerchi C, Inaba S, Le M, Miyazaki M, Glaser J, Correa-Rotter R, González MA, Aragón A, Wesseling C, Sánchez-Lozada LG, Johnson RJ - Kidney Int. (2013)

Dehydration causes renal dysfunction. (a) Urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine (Cr) ratio. (b) Serum creatinine (measured by high-performance liquid chromatography (HPLC)). Data represent analysis of variance (ANOVA) (Bonferroni post test) *P<0.05. CON, control; KHK-KO, fructokinase knockout; WAN, water at night; WAT, water all time.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120672&req=5

fig3: Dehydration causes renal dysfunction. (a) Urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine (Cr) ratio. (b) Serum creatinine (measured by high-performance liquid chromatography (HPLC)). Data represent analysis of variance (ANOVA) (Bonferroni post test) *P<0.05. CON, control; KHK-KO, fructokinase knockout; WAN, water at night; WAT, water all time.
Mentions: As shown in Figure 2 the WT mice that were dehydrated during the day without water (the WAN group) constituted the group that showed evidence for an increase in aldose reductase activity, as noted by an increase in renal sorbitol and fructose levels. This was also the only group that showed evidence of renal injury, as noted by an increase in urinary neutrophil gelatinase-associated lipocalin (Figure 3a), serum creatinine (Figure 3b), and evidence of proximal tubular injury by renal histology (Figure 4), and with a loss of proximal tubular brush border based on staining for angiotensin-converting enzyme using computer image analysis (Figure 5). Injury was present in both proximal tubules in the renal cortex and in the outer stripe. The injury was not due to rhabdomyolysis, as serum creatine phosphokinase levels at the time of killing were normal in all mice regardless of group (creatine phosphokinase levels <10 ng/ml). Consistent with the known effects of fructose to stimulate the chemokine monocyte chemotactic protein-1 (MCP-1) in proximal tubular cells,10 we also found both an increase in renal cortical MCP-1 levels (Figure 6a) and an increase in infiltrating macrophages in the WAN group compared with the other groups of WT mice (Figure 6b) as we can see in the F4/80 stain (Figure 7). An increase in interstitial fibrosis (collagen III staining) was also observed in the WT WAN group (Figures 8 and 9).

Bottom Line: Both groups received the same total hydration in 24 h.This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels.These studies provide a potential mechanism for Mesoamerican nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA.

ABSTRACT
The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Show MeSH
Related in: MedlinePlus