Multi-omics Analysis of Kidney Tissue Metabolome and Proteome Reveals the Protective Effect of Sheep Milk Against Adenine-Induced Chronic Kidney Disease in Mice.

Chronic kidney disease (CKD) is characterized by impaired renal function and is associated with inflammation, oxidative stress, and fibrosis. Sheep milk contains several bioactive molecules with protective effects against inflammation and oxidative stress. In the current study, we investigated the potential renoprotective effects of sheep milk and the associated mechanisms of action in an adenine-induced CKD murine model. Sheep milk delayed renal chronic inflammation (e.g., significant reduction in levels of inflammatory factors Vcam1, Icam1, Il6, and Tnfa), fibrosis (significant reduction in levels of fibrosis factors Col1a1, Fn1, and Tgfb), oxidative stress (significant increase in levels of antioxidants and decrease in oxidative markers), mineral disorders, and renal injury in adenine-treated mice (e.g. reduced levels of kidney injury markers NGAL and KIM-1). The combined proteomics and metabolomics analyses showed that sheep milk may affect the metabolic processes of several compounds, including proteins, lipids, minerals, and hormones in mice with adenine-induced chronic kidney disease. In addition, it may regulate the expression of fibrosis-related factors and inflammatory factors through the JAK1/STAT3/HIF-1 alpha signaling pathway, thus exerting its renoprotective effects. Therefore, sheep milk may be beneficial for patients with CKD and should be evaluated in preclinical and clinical studies. Sheep milk improves physiological and biochemical indices of chronic kidney in mice. Renal proteomics and metabolomics results indicate that sheep milk can affect signaling pathways such as protein, fatty acid, mineral, hormones and HIF.