Mechanisms of divergent NHE1 function in renal tubule versus cardiac myocyte cells

Project: Research

Investigators

  • Bassam G Abu Jawdeh (PI)

Description

Chronic kidney disease (CKD) is estimated to affect 27 million people in the U.S., and tubular atrophy is a strong predictor of CKD progression toward end stage renal disease (ESRD). CKD is considered a major risk factor for cardiovascular disease, which is the most common cause of death in the U.S. We have shown that tubular atrophy is due, at least in part, to apoptosis of renal tubule epithelial cells (RTC). The NHE1 Na+/H+ exchanger inhibits RTC apoptosis by enhancing Na+/H+ exchange, which helps to restore cell volume and inhibit activation of pH-sensitive cell death enzymes, as well as by functioning as a scaffold for a signaling complex that culminates in activation of the cell survival kinase, Akt. Although these data suggest that NHE1 would be an attractive therapeutic target for arresting CKD progression, NHE1 activation has also been implicated in cardiac myocyte cell death in the context of myocardial infarction. The goal of this proposal is to identify why NHE1 has divergent effects in cardiac myocytes and RTC cell survival. We hypothesize that upon NHE1 activation, there is an initial rise in intracellular Na+, which triggers cell-specific responses that regulate apoptosis. In myocardial cells, compensatory events include reverse mode Na+-Ca2+ exchange (Na+ out, Ca2+ in), which causes mitochondrial Ca2+ accumulation and apoptosis. In PTC, Na+-Ca2+ exchange is not as robust, and increases in intracellular Na+ and Ca2+ are not only better tolerated, but Na+ influx is actually desirable for reversal of apoptotic cell volume decreases. The aims of my proposal are: (1) To characterize effects of NHE1 activation on cell survival in PTC vs. cardiac myocytes, and (2) To determine reverse mode NCX1 activity and mitochondrial Ca2+ toxicity in PTC vs. cardiac myocytes in response to apoptotic stress.
Award amount$88,000.00
Award date07/01/2008
Program typePostdoctoral Fellowship
Award ID0825538D
Effective start/end date07/01/200806/30/2010
StatusFinished