The renal thick ascending limb contributes to the maintenance of acid-base homeostasis by reabsorbing both bicarbonate and ammonium. Our long-term goal is to understand the cellular, biochemical, and molecular mechanisms by which these transport processes are regulated. The central hypothesis of this proposal is that the control of HCO3 absorption in the medullary thick ascending limb (MTAL) depends on the regulation of both apical and basolateral Na+/H+ exchangers. We have developed evidence of a novel mechanism for regulation of HCO3 absorption in the MTAL, in which the activity of the apical Na+/H+ exchanger, which is directly involved in HCO3 absorption, is regulated by the activity of the basolateral Na+/H+exchanger. The current studies are directed toward understanding the mechanism whereby basolateral Na+/H+ exchange regulates apical Na+/H+ exchange, and identifying physiological factors and signaling pathways that regulate cross-talk between the exchangers. Preliminary studies show that the cross-talk mechanism is genetically eliminated in MTAL from NHE1 knockout mice, which will be studied to define the role of basolateral Na+/H+ exchange in regulating apical Na+/H+exchange and HCO3 absorption.
The Specific Aims i nclude: 1) determine the role of the actin cytoskeleton in mediating regulation of the apical Na+/H+ exchanger by the basolateral Na+/H+ exchanger, 2) examine chronic regulation of the interaction between basolateral and apical Na+/H + exchangers by changes in dietary Na+ intake, and 3) examine acute regulation of cross-talk between the exchangers by growth factors and aldosterone via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent pathways. Biochemical analyses and fluorescence microscopy will be integrated with ion transport measurements in MTALs microdissected from rats and gene-targeted mice to provide a detailed understanding of the cross-talk mechanism and its role in HCO3 absorption. These studies will identify novel mechanisms for the regulation of Na+/H + exchange activity and acid secretion in renal tubules and will investigate a new biological process involving cross-talk between Na+/H+ exchangers in basolateral and apical membranes of epithelial cells. The results will enhance our understanding of the role of the MTAL in the physiological and pathophysiological control of acid-base balance. In addition, they will be the first to identify a function for NHE1 in transepithelial transport in the kidney and to define a role for this basolateral exchanger in the acute and chronic regulation of HCO3 absorption.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK038217-19S1
Application #
7892833
Study Section
General Medicine B Study Section (GMB)
Program Officer
Ketchum, Christian J
Project Start
1987-07-01
Project End
2010-05-31
Budget Start
2009-07-17
Budget End
2010-05-31
Support Year
19
Fiscal Year
2009
Total Cost
$279,898
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Watts 3rd, Bruns A; George, Thampi; Sherwood, Edward R et al. (2018) Monophosphoryl lipid A prevents impairment of medullary thick ascending limb [Formula: see text] absorption and improves plasma [Formula: see text] concentration in septic mice. Am J Physiol Renal Physiol 315:F711-F725
Watts 3rd, Bruns A; George, Thampi; Sherwood, Edward R et al. (2017) Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway. Am J Physiol Renal Physiol 313:F103-F115
Watts 3rd, Bruns A; George, Thampi; Badalamenti, Andrew et al. (2016) High-mobility group box 1 inhibits HCO3- absorption in the medullary thick ascending limb through RAGE-Rho-ROCK-mediated inhibition of basolateral Na+/H+ exchange. Am J Physiol Renal Physiol 311:F600-13
Good, David W; George, Thampi; Watts 3rd, Bruns A (2015) High-mobility group box 1 inhibits HCO(3)(-) absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway. Am J Physiol Renal Physiol 309:F720-30
Watts 3rd, Bruns A; George, Thampi; Sherwood, Edward R et al. (2013) A two-hit mechanism for sepsis-induced impairment of renal tubule function. Am J Physiol Renal Physiol 304:F863-74
Watts 3rd, Bruns A; George, Thampi; Good, David W (2013) Lumen LPS inhibits HCO3(-) absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+ exchange. Am J Physiol Renal Physiol 305:F451-62
Good, David W; George, Thampi; Watts 3rd, Bruns A (2012) Toll-like receptor 2 is required for LPS-induced Toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J Biol Chem 287:20208-20
Good, David W; George, Thampi; Watts 3rd, Bruns A (2011) High sodium intake increases HCO(3)- absorption in medullary thick ascending limb through adaptations in basolateral and apical Na+/H+ exchangers. Am J Physiol Renal Physiol 301:F334-43
Watts 3rd, Bruns A; George, Thampi; Sherwood, Edward R et al. (2011) Basolateral LPS inhibits NHE3 and HCOFormula absorption through TLR4/MyD88-dependent ERK activation in medullary thick ascending limb. Am J Physiol Cell Physiol 301:C1296-306
Good, David W; George, Thampi; Watts 3rd, Bruns A (2010) Toll-like receptor 2 mediates inhibition of HCO(3)(-) absorption by bacterial lipoprotein in medullary thick ascending limb. Am J Physiol Renal Physiol 299:F536-44

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