Cellular Mechanisms of Injury in Acute Renal Failure: (Drs. Borkan and Schwartz)

Although ischemia is a common cause of acute renal failure (ARF), the cellular pathogenesis of injury is unknown and no therapeutic interventions presently exist. Recent investigations in Dr. Borkan’s and other laboratories have suggest that the kidney in vivo and cultured cells in vitro respond to ischemia by producing a host of “stress proteins”. These proteins include the heat stress proteins (HSPs), well-known “cell protectants” that may be capable of preventing or ameliorating acute renal failure if increased prior to the insult. Current studies are intended to quantify the protection afforded by HSP 70 by selectively manipulating the content of the wild type hsp70 and several of its well-characterized mutants. This model system is being used to dissect the potential mechanisms by which HSPs protect the cell from ischemic injury. We are presently investigating the interaction between hsp70 and members of the BCL2 family, as well as identifying the events that result in mitochondrial membrane injury, a key step in triggering the apoptotic cascade that results in cell death.

Selected References

  1. Haiping Mao, Fanghong Li, Kathleen Ruchalski, Dick D. Mosser, John H. Schwartz , Yihan Wang, and Steven C. Borkan. Hsp72 Inhibits Focal Adhesion Kinase Degradation in ATP-depleted Renal Epithelial Cells J. Biol. Chem 278: 18214 ¡V 18220, 2003.
  2. Ruchalski, K, Mao H, Singh S, Wang Y, Mosser DD, Li F, Schwartz, J and Borkan SC. HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells. Am J Physiol Cell Physiol 285: C1483-C1493, 2003.
  3. Mao, H, Wang, Y, Li, Zhijian, Ruchalski, KL, Yu, X, JH Schwartz and SC Borkan. Hsp72 interacts with paxillin and facilitates the reassembly of focal adhesions during recovery from ATP depletion J. Biol Chem 279: 15, 15472-15480, 2004.
  4. Sinha, D., Wang, Z., Ruchalski, K. L., Levine, J. S., Krishnan, S., Lieberthal, W., Schwartz, J.H., Borkan, S. C. Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors. Am J Physiol (Renal), 288; F703-13, 2004.
  5. Peng, X., et al., Heat shock protein 90 stabilization of erbB2 expression is disrupted by ATP depletion in myocytes. J Biol Chem 280; 13148-52, 2005.
  6. Schaefer KL, Wada, K,Takahashi, H, Matsuhashi N, Ohnishi, S Gijsbert van Seventer, Wolfe, MM, Turner JR, Nakajima A, Borkan SC, and Saubermann LL. PPARƒ× inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma Cells. Cancer Res 65; 2251-9, 2005.
  7. Ruchalski, K., Mao, H., Li, Z., Wang, Z., Gillers, S., Wang, Y., Mosser, D.D., Gabai, V., Schwartz, J.H. and Borkan, S.C. Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation. J Biol Chem 281:7873-7880, 2006