T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage

Figure 3

Therapeutic approaches to prevent peritoneal damage using the Th17/Treg-axis as a target. One of the most important modulators of Th17/Treg activity is the concentration of branch chain amino acids (BCAA). Although the data in relation to BCAA plasma levels in a uraemic state are contradictory, many articles indicate that these amino acids are decreased in uraemia due to systemic acidosis, inflammation, amino acid misbalances, and liquid overload. Normal or relative normal BCAA levels activate an mTOR (mammalian Target of Rapamycin) cascade including HIF1 and RORγt and subsequently IL-17 and IL-23 production. Rapamycin, an mTOR inhibitor, would block this cascade, thus providing an anti-inflammatory/antifibrotic and possibly anti-MMT effect. Moreover, PPARγ agonists can also inhibit Th17 differentiation through a direct blockade of Stat3 transcription factor and HIF-1. Ultimately RORγt is downregulated, and IL-17 and IL-23 production is decreased. However the PPRAγ agonists are also able to act on the anti-inflammatory cascade. In the peritoneal cavity in PD, rosiglitazone augments IL-10 levels and Treg activity (upregulation of FoxP3⁺). This process could be one of the most important mechanisms by which PPRAγ agonists protect the PM. In addition, paricalcitol, a specific vitamin D activator, has been recently shown to inhibit IL-17 production and PM fibrosis and possibly decrease MMT. Finally, celecoxib, a Cox2 inhibitor, decreases IL-17 production by blocking the E2 prostaglandin levels and thus attenuates the PM damage induced by PDF.