Contrast-induced nephropathy (CIN) is one of the most common causes of in-hospital acute kidney injury (AKI). Despite all the advances in the understanding of the pathogenesis of AKI, CIN treatment is very limited with no consensus on overall management. Therefore, there is a need for further characterization of the pathogenesis of CIN in order to establish a more efficient available treatment that can accelerate kidney recovery post-injury. High glucose levels (diabetes), hypertonic contrast agents and a hypoxic environment are common risk factors that significantly contribute to CIN 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. Of interest, as well as for CIN, hyperglycemia, hypertonicity and hypoxia are the main stimulants of aldose reductase expression and the activation of the polyol pathway. Data obtained by the PI of this proposal demonstrate that the activation of the polyol pathway in the kidney, the production of endogenous fructose and its metabolism through fructokinase are important events in the pathogenesis of ischemic AKI. Furthermore, our preliminary data in mice undergoing CIN show that 1) there is a significant activation of the polyol pathway and fructokinase in CIN. 2) Mice who cannot metabolize fructose in the kidney are protected against CIN with reduced generation of uric acid, oxidants and tubulointerstitial injury. These observations have lead the PI to his overall hypothesis of this application in that in contrast-induced nephropathy there is an activation ofaldose reductase and the polyol pathway and fructokinase which contributes to proximal tubule cell death. This hypothesis is a natural step forward from the K award for the PI to understand the specific role of endogenous fructose metabolism in the pathogenesis of AKI. The significance of this proposal is that inhibition of the polyol pathway is feasible in patients with acute kidney injury due to the availability of inhibitos (epalrestat, ranirestat). The innovation of this proposal is that a role for endogenous fructose and renal fructokinase has never been considered in contrast-induced nephropathy. This work is designed to enable the PI to establish independence and R01 funding in the following ways: Thorough characterization of the polyol pathway and fructokinase in a different but parallel model of acute kidney injury (contrast-induced nephropathy) than the one the PI is working on his current K award (ischemic AKI) will broaden the knowledge and the relevance of the PI's studies. If the hypothesis proposed in this application are correct, the work that the PI has been developing in the last 3 years and that will be expanded with this RO3 will have an immediate clinical impact in patients with concomitant risk factors (hyperglycemia) for AKI and/or CIN.
Contrast-induced nephropathy (CIN) is a common cause of in-hospital acute kidney injury (AKI) accounting for 20 % of cases in diabetics with no consensus on overall treatment. Published and preliminary data obtained by the PI in his K award demonstrate that endogenous fructose production and its metabolism in the kidney through fructokinase are important events in the pathogenesis of both AKI and CIN. This research proposal will study whether the blockade of endogenous fructose production by the polyol pathway (experiment 1) and its metabolism by fructokinase (experiments 2 and 3) exert protection in CIN and if our hypothesis is correct, blockade of this pathway could be clinically relevant not only as means to prevent contrast-induced nephropathy, but as a target to accelerate renal recovery after the onset of renal injury, and will therefore broaden the knowledge and the relevance of the PI's studies toward his future independence.
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