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.
p-Methylphenyl potassium sulfate是一种与慢性肾病进展、心血管风险和死亡率相关的原型蛋白质结合尿毒症毒素，来源于肝脏的酪氨酸和苯丙氨酸代谢产物[1,2]。p-Methylphenyl potassium sulfate的血清水平与肾功能衰竭的进展[3]、心血管风险和死亡率相关[4]。p-Methylphenyl potassium sulfate毒性机制包括促进炎症反应以及导致内皮功能障碍[5,6]。
在体外，p-Methylphenyl potassium sulfate（0.05、0.125、0.25、0.5mM）处理原代成骨细胞24小时，通过激活c-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（p38 MAPK）通路，导致甲状旁腺激素1型受体（PTHR）下调，从而导致成骨细胞功能障碍[7]。
在体内，p-Methylphenyl potassium sulfate（10mg/kg）腹腔注射给药于通过5/6肾切除诱发的慢性肾病（CKD）模型小鼠，每天给药两次连续治疗4周后，p-Methylphenyl potassium sulfate加重CKD小鼠的胰岛素抵抗，直接激活（细胞外信号调节激酶1/2）ERK1/2激酶，抑制胰岛素信号通路[8]。