Diabetic kidney disease (DKD) is a common and devastating complication in diabetic patients, which is recognized as a large and growing problem leading to end-stage kidney disease. As dietary-mediated therapies are gradually becoming more acceptable to patients with DKD, we planned to find active compounds on preventing DKD progression from dietary material. The present paper reports the renoprotective properties and underlying mechanisms of ginsenoside compound K (CK), a major metabolite in serum after oral administration of ginseng. CK supplementation for 16 weeks could improve urine microalbumin, the ratio of urinary albumin/creatinine and renal morphological abnormal changes in db/db mice. In addition, CK supplementation reshaped the gut microbiota by decreasing the contents of Bacteroides and Paraprevotella and increasing the contents of Lactobacillu and Akkermansia at the genus level, as well as reduced histidine-derived microbial metabolite imidazole propionate (IMP) in the serum. We first found that IMP played a significant role in the progression of DKD through activating toll-like receptor 4 (TLR4). We also confirmed CK supplementation can down-regulate IMP-induced protein expression of the TLR4 signaling pathway in vivo and in vitro. This study suggests that dietary CK could offer a better health benefit in the early intervention of DKD. From a nutrition perspective, CK or dietary material containing CK can possibly be developed as new adjuvant therapy products for DKD.

Diabetic kidney disease (DKD) occurs in 25–40% of patients with diabetes. Individuals with DKD are at a significant risk of progression to end-stage kidney disease morbidity and mortality. At present, although renal function-decline can be retarded by intensive glucose lowering and strict blood pressure control, these current treatments have shown no beneficial impact on preventing progression to kidney failure. Recently, in addition to control of blood sugar and pressure, a dietary approach has been recommended for management of DKD. Amino acids (AAs) are both biomarkers and causal factors of DKD progression. AA homeostasis contributes to renal hemodynamic response and glomerular hyperfiltration alteration in diabetic patients. This review discusses the links between progressive kidney dysfunction and the metabolic homeostasis of histidine, tryptophan, methionine, glutamine, tyrosine, and branched-chain AAs. In addition, we emphasize the regulation effects of special metabolites on DKD progression, with a focus on causality and potential mechanisms. This paper may offer an optimized protein diet strategy with concomitant management of AA homeostasis to reduce the risks of DKD in a setting of hyperglycemia.