The mammalian kidney is susceptible to injury by ischemia/reperfusion and toxins, and regeneration following injury is characterized by hyperplasia and recovery of the damaged epithelial cells lining the tubules. Endogenous growth factors may serve as mediator of renal regeneration following acute injury; exogenous administration of certain growth factors accelerate recovery of renal function. EGF receptor (EGFR) expression increases following acute renal injury, and administration of exogenous EGF accelerates recovery. Expression of another EGFR ligand, HB-EGF, increases in the kidney following injury. HB-EGF is expressed as an integral membrane protein that is cleaved to its soluble form following cellular activation. Membrane-associated proHB-EGF may also activate receptors on adjacent cells via juxtacrine signaling. We propose that proHB-EGF serves a trophic function to preserve and maintain epithelial cell integrity by two mechanisms: 1) juxtacrine signaling through EGFR; and 2) interaction with other membrane-associated and cytoskeletal elements. Cleavage of proHB-EGF may lead to cell activation by two complementary mechanisms: a) by release of soluble HB-EGF, an autocrine and paracrine growth factor that induces a cellular program eventuating in proliferation and dedifferentiation; and b) by disruption of cell-cell cell-EDC and cytoskeletal interactions of proHB-EGF and its associated proteins, thereby predisposing the epithelial cell to motility, proliferation and dedifferentian. We also hypothesize that endogenous sHB-EGF is important for recovery from acute injury, while sustained overexpression of HB-EGF in the proximal tubule may mediate chronic tubulointersitial injury and transdifferentiation.
Three specific aims are proposed.
In Specific Aim #1, processing of proHB-EGF and juxtacrine interactions of proHB-EGF and EGFR in polarized renal epithelial cells will be examined. We will examine signaling pathways activated by juxtacrine vs paracrine signaling, especially signaling events mediating cytoprotection and will investigate the role in signaling of proteins that interact with proHB-EGF.
Specific Aim #2 will determine the role of the HB-EGF/EGFR axis in tubular injury in vivo. Acute renal injury will be studied in a model of EGFR dysfunction, waved2. In order to examine the effects of HB-EGF on modulation of acute and chronic tubular injury, transgenic mice overexpressing HB-EGF will be generated.
Specific Aim #3 will examine the expression and function of HER4 in the kidney in response to epithelial injury and will examine the role of HER4 in mediating HB-EGF actions. In summary, these studies are designed to elucidate potential mechanisms by which the mammalian kidney repairs itself after acute injury, which may provide new insights into potential treatment strategies for acute and chronic tubulointersitial injury.
Showing the most recent 10 out of 107 publications
