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Acid-activated signaling pathway.
The overall focus of our laboratory is to elucidate the acid-activated signaling pathway that mediates the physiological response of the renal proximal tubule to the need for the kidney to excrete acid. A typical Western diet is acid-laden, with much of the acid load coming from the metabolism of ingested animal protein. In order to maintain systemic acid-base balance, the non-volatile portion of this acid load must be excreted by the kidney with equivalence between daily production and excretion. This is accomplished in two ways, one being regulation of base excretion (bicarbonate and citrate) and the other being regulation of acid excretion (titrated acids and ammonium). The proximal tubule of the kidney contributes to these processes by increasing proton secretion (primarily for bicarbonate reabsorption), ammonia synthesis and secretion, and citrate reabsorption. Using both whole animal and cell culture models of a decrease in cell pH (the signal that initiates the physiological response), we are identifying and ordering the signaling intermediates that mediate the increase in apical membrane proton secretion by the Na/H antiporter isoform NHE3 and citrate reabsorption by the Na-dicarboxylate co-transporter NaDC-1. We have found that acid regulation of both transporters is mediated by endothelin-1 signaling through the endothelin B receptor, have identified the non-receptor tyrosine kinase Pyk2 as a pH sensor for initiating the pathway the mediates stimulation of NHE3 activity, and demonstrated that the increase in NHE3 activity is dependent on exocytic movement of NHE3 to the apical membrane of the proximal tubule, a process that is RhoA dependent and involves formation of stress fibers and focal adhesions. Recent studies, using microarray analyses, have identified the circadian gene Nocturnin as involved in the physiological response. Current studies are: 1) elucidating the mechanism of the exocytic process of NHE3 trafficking, 2) identifying similarities and differences in acid regulation of NHE3 and NaDC-1 activities, and 3) determining the role circadian rhythm genes play in the regulation of the kidney’s ability to excrete an acid load.
Recent publications:
* authors contributed equally to the manuscript.
Amanzadeh, J., Gitomer, R., Zerwekh, J. E., Preisig, P. A., Moe, O. W, Pak, C. Y. C., and Levi, M. Effect of high protein diet on stone-forming propensity and bone loss in rats. Kidney Int 64:2142-2149, 2003.
Licht, C., K. Laghmani, M. Yanagisawa, P.A. Preisig*, and R.J. Alpern*. An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3. Kidney Int 65:1320-1326, 2004.
Aruga, S., A. Pajor, K. Nakamura, L. Liu, O.W. Moe, P.A. Preisig*, and R.J. Alpern*. OKP cells express the Na dicarboxylate cotransporter NaDC-1. Am. J. Physio., 287:C64-C72, 2004.
Li, S., S. Sato, X. Yang, P.A. Preisig * , and R.J. Alpern *. Pyk2 is a pH sensor signaling acid activation of NHE3 in OKP cells. J. Clin Invest 114:1782-1789, 2004.
Laghmani, K., A. Sakamoto, M. Yanagisawa, P.A. Preisig*, and R.J. Alpern*. A consensus sequence in the endothelin B receptor second intracellular loop is required for NHE3 activation by endothelin-1. Am. J. Physio., 288:F732-F739, 2005.
Yang, X., H. Yin, R.J. Alpern *, and P.A. Preisig*. Rho A mediates acid-induced stress fiber formation and trafficking and activation of NHE3. In revision.
Zhu, Z., C. Green, J. Besharse, R.J. Alpern * , and P.A. Preisig*. The circadian gene Nocturnin is acid-regulated and modifies proximal tubule response to dietary acid intake. In preparation.
Liu, L., M. Yanagisawa, R.J. Alpern * , and P.A. Preisig *. Acid regulation of proximal tubule citrate transport is mediated by endothelin-1 signaling through the endothelin B receptor. In preparation.
Li, S., H-C. Huang, R.J. Alpern * , and P.A. Preisig *. Ordering of acid-regulated signaling intermediates in mediating acid regulation of NHE3 activity. In preparation.
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patricia.preisig@yale.edu
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