Intercalated Cell Physiology Laboratory
Intercalated cells make up only about 1% of total kidney volume and yet have a marked effect on blood pressure and salt and water homeostasis. The Wall Laboratory, led by Division of Renal Medicine faculty member Susan Wall, MD, is exploring the signaling transduction mechanisms whereby this cell type mediates this function. To do so, they are using a variety of molecular biology and transport techniques both in cultured cells as well as in native tissue taken from a variety of genetically manipulated mice.
The Wall Laboratory is exploring blood pressure regulation by the kidney. In particular, they are addressing how intercalated cells, a minority cell type in kidney, controls blood pressure and the pressor response to hormones such as aldosterone and angiotensin II.
Until about 15 years ago, the function of renal intercalated cells was thought to be maintenance of acid-base balance. At that time, Dr. Wall and her colleagues made the striking observation that intercalated cells are instead critical in blood pressure regulation. In particular, they observed that the intercalated cell Cl-/HCO3- exchanger, pendrin, mediates Cl- absorption and HCO3- secretion. Moreover, this pendrin-mediated Cl-/HCO3- exchange, is greatly upregulated by aldosterone and angiotensin II. In the absence of pendrin (pendrin knockout mice), Cl-/HCO3- exchange process is diminished. Moreover, basal levels of blood pressure as well as the pressor response to aldosterone and angiotensin II are reduced in these mutant mice. The fall in blood pressure observed in pendrin null mice occurs at least in part because these mutant mice excrete more Na+ and Cl- than pair-fed wild type mice. The chloriuresis observed in the NaCl-restricted pendrin null mice could be readily explained by the absence of pendrin-mediated Cl- absorption. However, since pendrin does not transport Na+, the cause of the natriuresis was explored further. Although pendrin and ENaC localize to different cell types, Dr. Wall and her colleagues made the surprising observation that ENaC abundance and function are greatly reduced in pendrin null mice.
In further studies, she and her colleagues demonstrated that pendrin modulates ENaC abundance and function in aldosterone-treated mice, at least in part, by secreting HCO3- into the luminal fluid, which stimulates ENaC abundance and function.
Ongoing work by the Wall Laboratory involves teasing out the signaling mechanism whereby aldosterone and angiotensin II stimulate pendrin and other intercalated cell transporters. To do so, they combine a variety of techniques which employ molecular biology, imaging, and renal tubules perfused in vitro. They study in cells in culture as well as native tissue from wild type and transgenic micecells in culture as well as native tissue from wild type and transgenic mice.
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