Diabetic kidney disease is a major cause of renal failure with urgent need for a breakthrough of management. Diabetes causes significant changes in an array of plasma metabolites, and in the humans, renal SLCO4C1 in the proximal tubules is the only transporter contributes to transport them into urine. We found that phenyl sulfate (PS) was increased with the progression of diabetes and was decreased in Tg rats with limited proteinuria. In diabetes models, PS administration induced albuminuria with podocyte damage due to the mitochondrial dysfunction, suggesting the cause of renal damage in DKD.
In the gut, phenol is synthesized from tyrosine by gut bacterial-specific tyrosine phenol-lyase (TPL) and phenol is metabolized to PS in the liver. We then administered TPL inhibitor and found the reduction not only serum PS level but also albuminuria in diabetic mice. TPL inhibitor also ameliorated renal dysfunction in adenine-induced renal failure model without changing gut microbial community.
In a diabetic patient cohort (U-CARE, n=362), the serum PS level was related with the basal albuminuria level. Logistic regression analysis showed that among known ACR predictive factors, PS was the only factor which related 2-year progression of albuminuria in patients with microalbuminuria. These data suggested that PS is not only a modifiable cause but an early diagnosis marker, therefore a target for the treatment of DKD. Reduction of phenol production should represent another aspect for developing drugs preventing for DKD.