p-Methylphenyl potassium sulfate is a prototype protein-binding uremic toxin associated with the progression of chronic kidney disease, cardiovascular risk and mortality, derived from tyrosine and phenylalanine metabolites in the liver[1,2]. The serum level of p-Methylphenyl potassium sulfate is associated with the progression of renal failure[3], cardiovascular risk and mortality[4]. The toxic mechanisms of p-Methylphenyl potassium sulfate include promoting inflammatory responses and causing endothelial dysfunction[5,6].
In vitro, primary osteoblasts were treated with p-Methylphenyl potassium sulfate (0.05, 0.125, 0.25, 0.5mM) for 24 hours by activating the c-Jun n-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. It leads to the down-regulation of parathyroid hormone type 1 receptor (PTHR), thereby causing osteoblast dysfunction[7].
In vivo, p-Methylphenyl potassium sulfate (10mg/kg) was intraperitoneally injected into mice with chronic kidney disease (CKD) model induced by 5/6 nephrectomy. After being administered twice a day for 4 consecutive weeks, p-Methylphenyl potassium sulfate aggravates insulin resistance in CKD mice, directly activates (extracellular signal-regulated kinase 1/2) ERK1/2 kinase, and inhibits the insulin signaling pathway[8].
References:
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[2] Gryp T, Vanholder R, Vaneechoutte M, Glorieux G. p-Cresyl Sulfate. Toxins (Basel). 2017 Jan 29;9(2):52.
[3] Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, Tzen CY, Wang YC, Lin CY, Wu MS. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant. 2011 Mar;26(3):938-47.
[4] Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, Temmar M, Choukroun G, Vanholder R, Massy ZA; European Uraemic Toxin Work Group (EUTox). Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2010 Apr;25(4):1183-91.
[5] Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J, Vanholder R. P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant. 2007 Feb;22(2):592-6.
[6] Meijers BK, Van Kerckhoven S, Verbeke K, Dehaen W, Vanrenterghem Y, Hoylaerts MF, Evenepoel P. The uremic retention solute p-cresyl sulfate and markers of endothelial damage. Am J Kidney Dis. 2009 Nov;54(5):891-901.
[7] Tanaka H, Iwasaki Y, Yamato H, Mori Y, Komaba H, Watanabe H, Maruyama T, Fukagawa M. p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways. Bone. 2013 Oct;56(2):347-54.
[8] Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, Massy Z, Glorieux G, Vanholder R, Dugenet Y, Soula HA, Fouque D, Soulage CO. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol. 2013 Jan;24(1):88-99.