Lactoferrin attenuates renal fibrosis and uremic sarcopenia in a mouse model of adenine-induced chronic kidney disease

Abstract

The prevalence of chronic kidney disease (CKD) continues to rise, highlighting the urgent need for effective therapeutic interventions to address its various complications including sarcopenia. Lactoferrin, a multifunctional iron-binding glycoprotein found in mammalian breast milk, exhibits various biological activities and holds potential for treating CKD and its complications. This study investigated the effects of lactoferrin on CKD progression, its complications, and underlying mechanisms. A mouse model of adenine-induced renal failure was used as a CKD model. Lactoferrin was administered during the same period as adenine administration to assess its preventative effect on the progression of CKD. In another experiment, lactoferrin was administered after the adenine administration period to examine its effect on already advanced CKD. Effects of lactoferrin on renal function, renal pathology, and muscle atrophy were evaluated. Additionally, mechanistic insights were explored through mRNA and protein expression profiling, gut microbiota characterization, and metabolomic analysis. Lactoferrin administration improved reduction of renal function, and mitigated renal atrophy, and tubulointerstitial damage, and ameliorated skeletal muscle atrophy in CKD mice. In the skeletal muscle, CKD induced aberrant activation of mTOR1, impaired autophagy, and disrupted branched-chain amino acid metabolism. This abnormal activation of the proteolysis pathways was ameliorated by lactoferrin. Furthermore, lactoferrin attenuated dysbiosis-induced production of microbiota-derived uremic toxins, thereby reducing the indoxyl sulfate accumulation in blood and muscle. These effects contributed to decreased renal damage and delayed sarcopenia progression. Collectively, these findings suggest that lactoferrin may serve as a promising preventive and therapeutic agent for CKD-associated sarcopenia via the gut-kidney-skeletal muscle axis.