Our research program focuses on examining the role of adenine-monophosphate protein kinase (AMPK) in modulating the fate of renal tubular cells (RTCs) in culture when exposed to acute injury, and in altering the severity of renal dysfunction following acute kidney injury (AKI) in vivo.
AMPK is a serine/threonine kinase that is activated by very small decreases in cell ATP and therefore acts as a sensitive “gauge” of cell energy stores. When activated, AMPK phosphorylates many downstream kinases, enzymes and transcription factors, which have complex effects on cell metabolism, cell proliferation and apoptosis. One well established effect of AMPK activation is the conservation of cell energy stores, mediated by inhibiting anabolic processes while stimulating energy producing pathways.
We have published evidence demonstrating, that AMPK activation reduces apoptosis of RTCs exposed to metabolic stress in vitro, and ameliorates the severity of AKI in mice in vivo. We have also reported, that preconditioning mice with a highly specific pharmacologic activator of AMPK substantially enhances the ameliorative effect of AMPK in AKI in mice. We are currently doing studies to elucidate the mechanisms responsible for these effects of pharmacologic activation of AMPK. Our findings thus far suggest that the pro-survival effects of AMPK activation are mediated in at least two ways; I) by stimulating glycolysis, and ii) by activating Akt, a kinase which plays a critical role in opposing apoptotic cell death.
Selected peer reviewed publications
1. Sinha D, Wang Z, Ruchalski KL, Levine JS, Krishnan S, Lieberthal, W. 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 Physiol 288: F703-713, 2005.
2. Bonegio RG, Fuhro R, Wang Z, Valeri CR, Andry C, Salant, D S., Lieberthal, W. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. JASN 16: 2063-2072, 2005.
3. Lieberthal W, Zhang L, Patel VA, Levine JS. AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation. Am J Physiol Renal Physiol 301: F1177-1192, 2011.
4. Lieberthal W and Levine JS. Mammalian target of rapamycin and the kidney. I. The signaling pathway. Am J Physiol Renal Physiol 303: F1-10, 2012.
5. Lieberthal W and Levine JS. Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications. Am J Physiol Renal Physiol 303: F180-191 2012.
7. Lieberthal W, Tang M, Zhang L, Viollet, B, Patel, V and Levine JS. Susceptibility to ATP depletion of proximal tubular cells cultured from mice lacking either the a1 or a2 isoforms of the catalytic domain of AMPK. BMC Nephrology, 14:251-259, 2013.
8. Lieberthal W, Tang M, Lusco M, Abate M, Levine JS. Preconditioning mice with activators of AMPK ameliorates ischemic acute kidney injury in vivo. Am J Physiol Renal Physiol. 311:F731-F9, 2016.