Diabetic kidney disease is a major cause of renal failure in urgent of breakthrough in disease management. Type 2 diabetes causes significant changes in an array of plasma metabolites, and in the humans, SLCO4C1 is the only transporter contributes to transport them into urine. We generated transgenic (Tg) rats overexpressing SLCO4C1 in the proximal tubule, a typical model for human renal excretion. Using this model, we characterize metabolites that are increased in diabetic wild type rats, but reduced in diabetic Tg rats.PS increase with the progression of diabetes and was decreased in Tg rats with limited proteinuria. In diabetes models, PS administration induced albuminuria and podocyte damage due to the mitochondrial dysfunction. Phenol is synthesized from tyrosine by gut bacterial-specific tyrosine phenol-lyase (TPL) and phenol is metabolized to PS in the liver. Administration of TPL inhibitor reduced not only serum PS level but also albuminuria in diabetic mice. Furthermore, TPL inhibitor significantly ameliorate renal dysfunction in adenine-induced renal failure model. Because TPL inhibitor did not alter the major composition, the non-lethal inhibition of microbial-specific enzymes has a therapeutic advantage with lower selective pressure for the development of drug resistance. We next confirmed whether PS also related with the diabetes and DKD progression in humans. In a diabetic patient cohort (U-CARE study, n=362), serum PS levels related with the basal albuminuria level. In addition, logistic regression analysis showed that among known ACR predictive factors, PS was the only factor which significantly related 2-year progression of albuminuria in patients with microalbuminuria. These data suggested that PS may have a potential as important predictive marker of DKD.PS is a modifiable cause and a target for the treatment of DKD. Chemical reduction of TPL should represent another aspect for developing drugs preventing DKD (Kikuchi et al. Nat. Commun. 10: 1835, 2019).
K. Kikuchi: None. T. Abe: None.