Mitochondria and metabolism in kidney disease

点击翻译按钮获取中文摘要

Modified Project Summary/Abstract Section BACKGROUND: Acute kidney injury (AKI) remains a major global public health burden. Its long-term sequelae include chronic and end-stage kidney disease. Over the first two cycles of this award, we have identified the mitochondrial biogenesis regulator PGC1 as a determinant of experimental AKI outcomes. Independent studies have not only verified PGC1-dependent renoprotection, but also extended this to protection against fibrosis following AKI. In the most recent cycle, we identified two candidate effectors of renoprotection downstream of PGC1: the metabolic cofactor NAD+ and the transcription factor EB (TFEB). The former’s amenability to clinical testing has resulted in encouraging results from observational and pilot interventional testing among actual AKI patients. The latter coordinates an intracellular program to remove damaged proteins and organelles, including injured mitochondria that can secondarily exacerbate tubular cell injury. TFEB activation is being pursued for therapeutic mitophagy in several clinical indications. HYPOTHESIS: We hypothesize that NAD+ and TFEB may promote long-term kidney protection following AKI. We propose to evaluate this hypothesis in two parallel aims. AIMS: In Aim 1, we will evaluate the contribution of de novo NAD+ biosynthesis in two AKI-to-fibrosis models: ischemia-reperfusion injury and crystal-induced nephropathy. The interventions here include an enzyme inhibitor compound being developed for clinical testing and an inducible renal tubular transgenic mouse that exhibits renoprotection in an acute setting. In Aim 2, we will define therapeutic windows for activation of TFEB after AKI as the initial insult transitions to scarring. This Aim will apply a pharmaceutical compound being developed for clinical testing in the same two models of AKI-to-fibrosis. CONCLUSION: Our long-term objective is to apply metabolic insights to improve renal health. We have developed the necessary tools and are fortunate to collaborate with recognized leaders for both Aims. Promising preliminary data supports each Aim. Understanding when and in what contexts activation of TFEB or repletion of NAD+ may attenuate AKI’s progression to fibrosis may not only deepen our fundamental understanding of metabolism’s impact on renal health, but also delineate potential avenues for future translational inquiry.