• PKC and ATR Mediated Regulation of Cisplatin-Induced Renal Tubular Cell Apoptosis

      Pabla, Navjotsingh; Department of Cellular Biology and Anatomy (2009-03)
      Cisplatin is one of the most widely used anti-cancer drug. However, its use and efficacy is limited due to nephrotoxicity. One fourth of patients treated with cisplatin develop varying degree of renal impairment, frequently resulting in acute kidney injury. Due to high mortality associated with acute kidney injury, effort has been made to understand the molecular basis of cisplatin nephrotoxicity and develop effective renoprotective strategies. In kidneys, cisplatin is accumulated in tubular cells; however the uptake mechanism that is responsible for high accumulation of cisplatin in renal cells is unclear. In tubular cell, cisplatin accumulation induces cell death by apoptosis. Mechanistically, our laboratory has demonstrated a critical role of p53 in tubular cell apoptosis during cisplatin nephrotoxicity. However, the proximal events that contribute to p53 activation and related signaling are unknown. The focus of my work was to decipher these early events during cisplatin nephrotoxicity. Firstly, my results suggest that the copper transporter Ctr1 is highly expressed in renal tubular cells and is responsible for renal uptake of cisplatin. Secondly, I show that DNA damage response involving ATR-Chk2 is responsible for p53 activation and consequent apoptosis during cisplatin-induced kidney injury and nephrotoxicity. Thirdly, I have identified that PKCd is a novel regulator of cisplatin nephrotoxicity. During cisplatin treatment PKCd is activated in a Src dependent manner and is responsible for activation of MAPKs, contributing to renal cell death. Most importantly, my results suggest that pharmacological inhibition of PKCd ameliorates renal injury without affecting the anticancer efficacy of cisplatin. These results have not only provided new insights into the 3 molecular mechanism of cisplatin nephrotoxicity, but have also identified a novel strategy to mitigate the side effects of cisplatin in normal renal tissues.