Mechanisms of Alcohol Toxicity and Kidney Damage

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Project Summary Alcohol consumption contributes to approximately 6% of worldwide deaths. There remains a pressing need for understanding the biochemical mechanisms underlying alcohol toxicity and kidney disease, as chronic alcohol ingestion has been shown to play a key role in the development of acute kidney injury associated with the mortality of alcohol-associated liver disease. It is undeniable that the effect of excessive alcohol consumption presents a direct route to kidney damage, yet the mechanisms underlying this effect remain unknown. This proposal integrates key preliminary data into an innovative hypothesis that alcohol metabolism leads to disrupted acetyl-dependent cellular signaling and altered gene expression profiles, contributing to proximal tubule damage and kidney disease. Alcohol metabolism is known to alter numerous biochemical pathways which leads to negative consequences throughout the cell, including altered genetic reprogramming and cell death. Therefore, alcohol-induced protein acetylation is likely a key initial driver of these changes and downstream kidney pathologies, such as proximal tubular dysfunction. Therefore, we present an innovative approach for investigating how alcohol toxicity induces kidney damage. We will investigate the proposed specific aims: Specific Aim 1: Determine how chronic alcohol consumption alters renal histone acetylation profiles and gene expression using tissue spatial transcriptomics. Specific Aim 2: Examine altered proximal tubule pathology and proteomic activity resulting from chronic alcohol metabolism. These aims will be interrogated utilizing a multidisciplinary approach that will integrate pathological analysis, quantitative mass spectrometry for proteomics, enzymatic assays, and tissue morphology gene expression, as well as innovative data analyses and bioinformatics. A key outcome of this research will be an enhanced understanding of the mechanisms by which alcohol metabolism impacts renal function to further therapeutic intervention and the amelioration of kidney disease.