Doctor of Philosophy (PhD)
Cellular & Integrative Physiology
Babu J. Padanilam
Acute kidney injury is a common clinical syndrome particularly in hospitalized patients. Necrotic cell death, as one type of major cell death after ischemic reperfusion injury, is partially responsible for the rapid decline in GFR. p53 is a novel apoptosis and necrosis inducer and is found to be activated after ischemic renal injury. Although previous studies suggest that p53 could be an important mediator of kidney dysfunction, no studies have examined its role in necrotic cell death and the cross talk between p53 and other necrotic cell inducers such as PARP-1 and CypD. Thus, in this study our first goal was to examine the effect of gene ablation of p53 specifically in the proximal tubules on ischemic renal injury. Our second goal was to examine the possible mechanism by which p53 may induce necrosis. Our third goal was to test if double knockout of PARP-1/CypD or PARP-1/p53 additively/synergistically protects kidney from ischemic injury. Our results suggest that knockout of p53 specifically in the proximal tubules protected the kidney form ischemic renal injury by reducing apoptotic/necrotic cell death, inflammation, and long term fibrosis. Further, we found that double knockout of PARP-1/CypD or PARP-1/p53 in the kidney had better protective effects than respective single knockout mice. In addition, kidneys from double knockout mice also have better histological findings and fewer necrotic tubules. Our data demonstrate that activation of p53 significantly increased PARP-1 expression, which could contribute to necrosis in tubular cells. Furthermore, activation of p53 significantly decreased the expression of SLC7A11, a Glu/Cys carrier in cell membrane that inhibits ferroptosis. This result suggests that p53-mediated ferroptosis might further contribute to tubular cell death after injury. Together, our data suggest that p53 is an important necrotic cell death inducer in ischemic renal injury. p53 may induce necrosis via overexpression of PARP-1 and Bax, and promote ferroptosis by reducing the expression of SLC7A11 to induce cell death after ischemic renal injury. Our findings may have clinical implications for the pathogenesis of acute kidney injury, possibly providing potential therapeutic targets for this devastating syndrome.
Ying, Yuan, "Molecular Mechanisms of Necrotic Cell Death in Ischemic Renal Injury" (2016). Theses & Dissertations. 80.