Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis

Abstract

Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that facilitate their urinary excretion, but the endogenous metabolites are hardly removed with kidney dysfunction and may contribute to CKD progression. Accumulating evidence suggests that senescence of kidney tubule cells influences kidney fibrosis, the common endpoint for CKD with an excessive accumulation of extracellular matrix (ECM). Senescence is a special state of cells characterized by permanent cell cycle arrest and limitation of proliferation, which promotes fibrosis by releasing senescence-associated secretory phenotype (SASP) factors. The accumulation of PBUTs in CKD causes oxidative stress and increases the production of inflammatory (SASP) factors that could trigger fibrosis. Recent studies gave some clues that PBUTs may also promote senescence in kidney tubular cells. This review provides an overview on how senescence contributes to CKD, the involvement of PBUTs in this process, and how kidney senescence can be studied. Finally, some suggestions for future therapeutic options for CKD while targeting senescence are given.

Gut Microbiota-derived Metabolites: A New Perspective of Traditional Chinese Medicine Against Diabetic Kidney Disease

“…[6] These uremic toxins enter the blood circulation through the damaged intestinal epithelial barrier, potentially activate intestinal mucosal immunity, and induce systemic micro-inflammatory response, which further aggravates kidney damage and ultimately leads to the progression of DKD to ESRD. [7] In particular, TMAO, as a low molecular weight substance, is mostly cleared by the kidneys through glomerular filtration and tubular secretion into urine. As DKD progresses, TMAO continues to accumulate in patients due to a decrease in glomerular filtration rate.…”

“…[5] An increasing amount of research evidence has shown that gut microbiota is closely related to DKD. [6][7][8][9][10] Due to a decrease in glomerular filtration rate in DKD, uremic toxins accumulate in patients' circulation, leading to an imbalance in the gut microbiota. This imbalance leads to an increase in harmful bacteria and a decrease in probiotics, which results in an increase in uremic toxins, such as indoxyl sulfate (IS), p-cresol sulfate (p-CS), trimethylamine, and trimethylamine N-oxide (TMAO), and a decrease in renal protective metabolites, such as short chain fatty acids (SCFAs).…”