Aging-associated renal disease in mice is fructokinase dependent

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.

High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism

“…A limitation of our study was that we used a genetically modified (fructokinase knockout) mouse to show a functional role of fructokinase in high-salt-mediated obesity. However, these mice show normal activity and development and have a normal life span (29). They are also protected against fructose-induced obesity (9) but not against obesity driven by a high-fat diet (30), which supports the finding that high-salt diets may induce obesity via endogenous fructose production.…”

Hydrogen sulfide ameliorates aging-associated changes in the kidney

“…We did not study other properties of H 2 S that may be potentially involved in amelioration of kidney injury, e.g., mitochondrial biogenesis and regulation of epigenetics (Weber et al 2017). In future, we will need to address the role of H 2 S in recently reported mechanisms of kidney injury in aging, e.g., podocyte deficiency leading to glomerulosclerosis, mitochondrial dysfunction, and fructose metabolism (Hodgin et al 2015;Roncal-Jimenez et al 2016;Sweetwyne et al 2017). Additionally, we did not test whether H 2 S prolongs life span in mice as has been shown in C elegans (Miller et al 2011;Miller and Roth 2007).…”

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…For example, resveratrol prolongs lifespan in the extremely short-lived killifish (90). We found that mice that cannot generate fructose, which are therefore protected from mitochondrial oxidative stress, were also protected from developing age-related renal disease (157). In theory, elevated expression of NRF2 also mimics caloric restriction, as knockdown of KEAP1 in mice results in accumulation of NRF2 and thus augments the activation of cellular stress responses, including fatty acid oxidation and lipogenesis (158) .…”