Acute kidney injury is a common cause of hospitalization with high mortality affecting 30% of patients admitted to the intensive care unit. After decades of important discoveries regarding its pathophysiology, no clinically applicable treatment to accelerate kidney recovery in acute kidney injury has emerged. The polyol pathway is a metabolic route constituted by two enzymes, aldose reductase and sorbitol dehydrogenase. Aldose reductase converts glucose to sorbitol while sorbitol dehydrogenase metabolizes sorbitol to fructose. Our preliminary data in mice with ischemic acute kidney injury demonstrate that there is a significant activation of the polyol pathway in the kidney cortex as noted by high level of aldose reductase, and fructose accumulation (endogenous fructose). Our published data demonstrate that in the kidney the metabolism of fructose by the enzyme fructokinase results in ATP depletion and the generation of uric acid and oxidants causing acute tubulointerstitial injury. These observations lead to the overall hypothesis of this application that ischemic acute kidney injury activates the polyol pathway and fructokinase which contributes to proximal tubule cell death. The significance of this proposal is that inhibition of the polyol pathway is feasible n patients with acute kidney injury due to the availability of inhibitors (epalrestat, ranirestat). Te innovation of this proposal is that a role for endogenous fructose and renal fructokinase has never been considered in ischemic acute kidney injury. The research design to study the deleterious role of the polyol pathway and endogenous fructose production and metabolism will involve the characterization of 1) the activation of the polyol pathway and its deleterious role in ischemic acute kidney injury by using wild type and aldose reductase deficient mice, 2) the activation of fructokinase and endogenous fructose metabolism and its deleterious role in ischemic acute kidney injury by utilizing wild type and fructokinase global and proximal tubule deficient mice and 3) the fructose downstream mechanisms that leads to proximal tubule dysfunction, injury and cell death by employing human proximal tubular cells, (HK-2). The applicant will rely on an excellent mentorship program with Dr. Richard Johnson as his primary Mentor. Dr Johnson is one of the leading researchers in fructose, uric acid and the role they play in endothelial dysfunction, metabolic syndrome and kidney disease. He is currently the Division Head and Professor of Medicine at the University of Colorado Denver, Division of Renal Diseases and Hypertension. In addition, Dr. Sarah Faubel, Associate Professor of Medicine, at University of Colorado Denver, is his secondary Mentor and a leading investigator in ischemic acute kidney injury with expertise in animal models, characterization of kidney injury and multiorgan dysfunction. The applicant will also rely on the expertise and technology from several consultants outside the Renal Division, Dr Mark Petrash, Professor and Vice Chair for Research, Department of Ophthalmology, who is a world expert on aldose reductase is serving as a collaborator, Dr Scott Lucia (Chief of Renal and genitourinary pathology) awill also act as collaborator in the assessment of kidney injury and Dr Bruce Molitoris, Professor of Medicine at Indiana University will assist Dr Lanaspa in the development of proximal tubule fructokinase deficient mice This award will allow the applicant to develop the skills necessary to become an independent scientist and will provide for intellectual development through both didactic programs and lectures and by facilitating interactions with a variety of researchers in different departments and institutions.
Acute kidney Injury is a common clinical complication accounting for 30-50 % admissions to the intensive care unit with no available treatment. Published data demonstrate that dietary fructose can cause acute kidney injury. This research proposal will focus in the deleterious role of endogenously produced fructose by the polyol pathway (Aim 1) and its metabolism by fructokinase (Aims 2 and 3). Stimulation of the polyol pathway and fructokinase induces ATP depletion, uric acid and oxidant generation thus being an amplifying force that contributes to proximal tubule cell death associated to ischemic acute kidney injury. If our hypothesis is correct, blockade of this pathway could be clinically relevant not only as means to prevent ischemic acute kidney injury (such as precardiovascular surgery), but as a target to accelerate renal recovery after the onset of renal injury.
|Andres-Hernando, Ana; Li, Nanxing; Cicerchi, Christina et al. (2017) Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat Commun 8:14181|
|Johnson, Richard J; Stenvinkel, Peter; Jensen, Thomas et al. (2016) Metabolic and Kidney Diseases in the Setting of Climate Change, Water Shortage, and Survival Factors. J Am Soc Nephrol 27:2247-56|
|Le, MyPhuong T; Lanaspa, Miguel A; Cicerchi, Christina M et al. (2016) Bioactivity-Guided Identification of Botanical Inhibitors of Ketohexokinase. PLoS One 11:e0157458|
|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|
|Bjornstad, Petter; Maahs, David M; Jensen, Thomas et al. (2016) Elevated copeptin is associated with atherosclerosis and diabetic kidney disease in adults with type 1 diabetes. J Diabetes Complications 30:1093-6|
|Kanbay, Mehmet; Jensen, Thomas; Solak, Yalcin et al. (2016) Uric acid in metabolic syndrome: From an innocent bystander to a central player. Eur J Intern Med 29:3-8|
|Bjornstad, Petter; Lanaspa, Miguel A; Ishimoto, Takuji et al. (2015) Fructose and uric acid in diabetic nephropathy. Diabetologia 58:1993-2002|
|Johnson, Richard J; Lanaspa, Miguel A; Gabriela Sánchez-Lozada, L et al. (2015) The discovery of hypertension: evolving views on the role of the kidneys, and current hot topics. Am J Physiol Renal Physiol 308:F167-78|
|Johnson, Richard J; Merriman, Tony; Lanaspa, Miguel A (2015) Causal or Noncausal Relationship of Uric Acid With Diabetes. Diabetes 64:2720-2|
|Roncal Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A et al. (2014) Fructokinase activity mediates dehydration-induced renal injury. Kidney Int 86:294-302|
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