The cyclopentenone prostaglandin 15‐deoxy‐Δ 12,14 prostaglandin J2 (15d‐PGJ2), a Peroxisome‐Proliferator‐Activated Receptor γ(PPARγ) agonist, induced apoptosis in rat proximal tubular cells (RPTC). Failure of PPARγ antagonists, GW9662 and T0070907, in preventing 15d‐PGJ2 induced apoptosis suggested that the apoptotic effect of 15d‐PGJ2 is independent of PPARγ agonist activity. Interestingly, N‐acetyl cysteine (NAC), N‐(2‐Mercapto propionyl) glycine (NMPG) and reduced glutathione (GSH), free thiol containing antioxidants, inhibited 15d‐PGJ2 induced apoptosis. In contrast, Tempol and Trolox, antioxidants which scavenge free radicals, failed to block apoptosis thus suggesting that disruption of the intracellular sulfhydryl homeostasis may be responsible for 15d‐PGJ2 mediated apoptosis in RPTC. Moreover, our results indicated that 15d‐PGJ2 induced apoptosis in RPTC was accompanied by decreased p53 and increased p21 expression suggesting that p21 upregulation is independent of p53. Furthermore, thiol antioxidants (NAC, NMPG and GSH) prevented the induction of p21 by 15‐d‐PGJ2 suggesting a redox‐dependent mechanism for p21 upregulation. In addition, overexpression of Bcl‐2, an antiapoptotic protein, blocked 15‐d‐PGJ2 induced apoptosis in RPTC. Role of Bcl‐2 in redox regulation and contribution of redox mechanisms in p21 upregulation are being currently explored. This work was supported by NIH grant DK54472 to P.S.