Chronic kidney disease (CKD) is increasing in prevalence and affects more than 20 million individuals in the United States, and is especially common among veterans. Some causes are well known, such as diabetes and hypertension, and current management remains similar to two decades ago and consists of blood pressure control, blood sugar control, and blockade of the renin angiotensin system. More recently, we find that CKD is developing in people before they develop diabetes and hypertension, such as in subjects with metabolic syndrome, and also is developing in almost everyone as we age. Furthermore, once we have CKD, progression of kidney disease tends to continue despite our best efforts. It seems like there must be some other risk factor that has not been identified. In this proposal we present a novel hypothesis that our western diet may be driving subtle kidney disease in everyone. Specifically, we suggest that a little-known enzyme in the kidney proximal tubule, known as fructokinase, may be driving much of the current CKD epidemic. Fructokinase is an enzyme that metabolizes fructose and in the process causes intracellular ATP depletion, oxidative stress, and an inflammatory response. Diets high in sugars containing fructose can cause acute and chronic kidney disease in rats, likely due to metabolism of fructose in the proximal tubule. Recently we found that fructose can also be generated from glucose in the proximal tubule when the enzyme aldose reductase is induced, and preliminary studies suggest this may have a role in diabetic and nondiabetic CKD and also in aging-associated CKD. We therefore hypothesize that low grade fructose metabolism by fructokinase in the proximal tubule is the missing link that explains why CKD is increasing, why CKD is associated with metabolic syndrome, why CKD is occurring with aging, and why kidney disease progresses in subjects with preexisting CKD. To test these hypotheses, we will do the following studies.
Aim 1 will evaluate the role of fructokinase in the CKD associated with aging and metabolic syndrome, and will also determine if CKD is accelerated by simple sugars containing fructose, sucrose, or glucose compared to complex carbohydrates. Models will include normal mice and mice with metabolic syndrome (Pound mouse) that either express fructokinase or have fructokinase systemically absent.
Aim 2 will determine if fructokinase has a role in the renal progression that occurs in established CKD and whether it is accelerated by simple sugars via this mechanism.
Aim 3 will test the hypothesis that it is renal fructokinase that is driving aging-associated CKD and the progression of kidney disease in established CKD using mice in which fructokinase is selectively deleted from the kidney. If successful, these studies will identify a novel mechanism driving CKD that could be as important a factor as hypertension and diabetes themselves. Furthermore, our studies should be able to determine if altering the composition of simple sugars in the diet can influence progression. These discoveries could therefore lead to both dietary measures, as well as potentially new treatments to prevent CKD in veterans and others living in western cultures.

Public Health Relevance

Chronic kidney disease (CKD) is common and increasing in our population, and affects more than 40% of individuals over 65 years of age. In addition to the well-studied causes of diabetes and hypertension, many cases of CKD occur in their absence, especially in subjects with metabolic syndrome or aging. Based on preliminary data, we hypothesize that nondiabetic CKD and aging-associated kidney disease are largely caused by western diets rich in simple sugars that engage the polyol-fructokinase pathway in the kidney. In this proposal we will study the effect of diet rich in simple sugars or complex carbohydrates on normal mice, mice with metabolic syndrome, mice with preexistent CKD, and aging mice to determine the role of diet in causing or accelerating their kidney disease and the role of fructokinase in this process. Our work should identify a novel role for carbohydrates and sugar in driving CKD and novel ways to prevent CKD. The impact on veterans, as well as all individuals on western diets, should be evident.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Nephrology (NEPH)
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VA Eastern Colorado Health Care System
United States
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Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A et al. (2016) Aging-associated renal disease in mice is fructokinase dependent. Am J Physiol Renal Physiol 311:F722-F730
Johnson, Richard J; Nakagawa, Takahiko; Sanchez-Lozada, L Gabriela et al. (2013) Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62:3307-15