Diabetic kidney disease (DKD) is a significant public health problem. Progression to end-stage renal disease (ESRD) leads to dramatic increases in morbidity and mortality. The mechanisms underlying progression of DKD are poorly defined and current noninvasive markers incompletely correlate with disease progression. Our recent human studies indicate that altered tubular mitochondrial nutrient metabolism, specifically higher levels of tricarboxylic acid (TCA) cycle intermediates, predicts progression of DKD. In contrast, lower urinary Tamm Horsfall Protein (THP) levels associate with human chronic kidney disease (CKD) progression, suggesting a protective role for THP. We also found that urinary THP is increased in a rodent hypoxia-induced kidney injury which exhibits mitochondrial damage, with increased levels of THP associated with protection from injury. In this proposal, we seek to link THP levels to mitochondrial function, identifying a protective role of THP on renal disease progression by utilizing complimentary rodent and human studies in DKD. These discovery studies will lay the groundwork for future large-scale prospective studies to identify the biomarker potential of urinary THP and tricarboxylic acid cycle metabolites and mechanistically define the link between THP and mitochondrial function. This work will further a collaborative infrastructure between PKUHSC and Michigan Medicine, and foster training of PKUHSC staff and graduate students in metabolomics.