Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Abstract

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD

“…2 Both p-cresyl sulfate and indoxyl sulfate have been repeatedly associated with mortality and cardiovascular disease in patients with CKD as supported by mechanistic studies. [4][5][6][7][8][9][10][11][12] Phenylacetylglutamine (PAG) is another recently identified colonic microbial metabolite from amino acid fermentation. It results from glutamine conjugation of phenylacetic acid, which is almost exclusively derived from the microbial conversion of phenylalanine.…”

Treatment of Drinking Water in Economical Cost Perspective

“…Chemical coagulation as treatment of drinking water with Aluminum Sulphate and FeCl 3 was very effective for removing toxins (shiga toxin, Botulinum toxin and Microcystins). Studies show that 90-98% toxins remove from drinking water samples by using the coagulant but boiling of drinking water treatment method remove 95% only [10,11,12]. Additionally, face washing can prevent and reduce the eye infections as Tacoma, the greatest reason of infectious of blindness across the world.…”

Targeting Immunity in End-Stage Renal Disease

“…These uremic toxins are increased in the advanced stages of renal disease and induce intercellular adhesion molecule-1 (ICAM-1) expression, activating NF-κB and reactive species production by endothelial cells [17], increasing leukocyte endothelial adhesion [18], endothelial E-selectin, MCP-1, and tissue factor expression [19]. …”