Daniel C. Biemesderfer PhD
Research Scientist in Medicine (Nephrology)
Proximal tubule; regulated intramembrane proteolysis; megalin; amyloid precursor protein
- Regulated intramembrane proteolysis of megalin.
- Functional role of the amyloid precursor protein and the amyloid precursor like protein-2 in the proximal tubule.
Employs cell and molecular biological methods to study mechanisms of protein and ion transport in the brush border of the proximal tubule.
Extensive Research Description
I have a long-standing interest in the molecular and cellular mechanisms that mediate ion transport and protein absorption in the proximal tubule. An important goal in our lab is trying to understand how these processes participate in renal disease. Most recently, we have identified signaling pathways in the proximal tubule that use a mechanism called regulated intramembrane proteolysis (RIP) that is thought to link events at the plasma membrane with regulated expression of specific genes. We recently showed that the proximal tubule scavenger receptor megalin is subjected to RIP and which in turn inhibits expression of specific brush border genes. In other studies designed to identify the metalloprotease that mediates megalin ectodomain shedding we found that ADAM10, a well known sheddase of other receptors (amyloid precursor protein and Notch) that initiates RIP, colocalizes with megalin in the brush border. Additional studies showed that, although ADAM10 is not the megalin sheddase, its activity does regulate expression of specific brush border proteins (see Preliminary Studies). We speculated that ADAM10 is part of an as yet undefined RIP-mediated signaling pathway in the proximal tubule. Data provided from studies funded by our current R21 (DK078710-01) show: (1) both the amyloid precursor protein (APP) and the amyloid precursor-like protein 2 (APLP2) are highly expressed in kidney and in cultured proximal tubule cells where they colocalize with ADAM10, (2) ADAM10 cleaves the ectodomain of APLP2 in OKP cells and, (3) physiological studies of APP-/- and APLP2-/- mice show important defects in kidney function (see Preliminary Data). Together, these data support our hypothesis that ADAM10, APP and APLP2 represent elements of a novel signaling pathway in proximal tubule that link events at the brush border with gene regulation. We also emphasize that since RIP of APP is thought to play a central role in the pathogenesis of Alzheimer Disease (AD) and because APP and the proteases that mediate RIP of APP and APLP2 are therapeutic targets for treating AD it will be important to understand how such therapies will affect renal function in the AD patient. PubMed Search for articles by faculty member