Classification of Five Uremic Solutes according to Their Effects on Renal Tubular Cells

Figure 8

Schematic diagram of the effects of uremic solutes on porcine renal tubular cells. Group 1 exclusively induces cell cycle delay, which would be mediated by oxidative stress and ER stress. IS is reported to induce oxidative stress [27–32] and ER stress [40]. Oxidative stress can cause DNA damage, which is followed by Chk1 and p53 activation [33]. Activated Chk1 can arrest cell cycle progression [34]. Activation of p53 by IS is also reported [29–32]. Activated p53 can repress transcription of Cdc20 [38] and Skp2 [36, 37]. Because both Cdc20 and Skp2 have important roles in cell cycle progression [35], their repression might delay cell cycle. Another downstream target of p53, p21, which is also an important regulator of cell cycle, is also reported to be induced by IS [31, 32, 40]. Meanwhile, ER stress can induce ATF4 and CHOP expression, which is followed by apoptosis [39]. However, it is also reported that IS induced CHOP expression and CHOP mediates inhibition of proliferation instead of induction of apoptosis in human renal tubular cells [40]. Thus, observed ATF4 and CHOP mRNA induction might be involved in cell cycle delay rather than apoptosis. Group 2 exclusively induces apoptosis, but its mechanism of action is largely unknown. Group 3 marginally induces both cell cycle delay and apoptosis, which might be partly mediated by p53 and ER stress. More detailed explanation is in Section 4. Cont, control; IS, indoxyl sulfate; PCS, p-cresyl sulfate; PhS, phenyl sulfate; HA, hippuric acid; IAA, indoleacetic acid; NAC, N-acetyl-L-cysteine. Number in brackets corresponds to the number of reference literature.