The thick ascending limb of the loop of Henle contributes to the renal regulation of systemic acid-base balance by reabsorbing both bicarbonate and ammonium. the continuing goal of this project is to determine the cellular and molecular mechanisms of these absorptive processes. Absorption of HCO3 by the medullary thick ascending limb (MTAL) is regulated by several factors (peptide hormones, growth factors, prostaglandins, catecholamines) associated with clinical acid-base disorders and renal disease states, but the mechanisms of this regulation are not understood. the overall goal of the current project is to identify the signal transduction pathways that regulate acide-base transport in the MTAL and to provide an integrated picture of the physiologic regulation ofHCO3 absorption. this requires analytical studies of diverse signaling pathways, focused on understanding how they function and interact in the MTAL. MTALs from rates will be studies in vitro to investigate four specific issues: I. Regulation of Na+/H+ exchange by protein kinase C, II. Regulation of Na+/H+ exchange and HC03 absorption by growth factors, III. Regulation of signaling via protein kinase C, and IV. Signaling via tyrosine kinawse pathways and mitogen activated protein kinases. A basic strategy of the project is that transepithelial transport rates, activities of apical and basolateral membrane transporters, effects of protein kinase inhibitors, and activities of individual signaling proteins will be measured coordinately in the MTAL to provide a detailed and integrative understanding of the regulation of HCO3 absorption. This approach will include newly developed methods for the measurement of protein kinase activities using immune complex assays in microdissected renal tubules. The proposed studies will provide new information on issues fundamental to understanding the physiology and pathophysiology of epithelial acid-base transport, including 1) the signaling proteins that couple extracellular stimuli to the regulation of apical and basolateral membrane acide-base transporters, 2) how different signaling pathways interact to regulate acide-base transport, and 3) several unusual aspects of the regulation of Na+/H+ exchange, including inhibition by hyperosmolatity and growth factors. These studies will be the first to examine in detail the signal transduction pathways that regulate acide-base transport in the mammalian thick ascending limb. The results will provide information essential for understanding the role of the thick ascending limb in the physiologic and pathophysiologic control of systemic acid-base balance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038217-12
Application #
2734056
Study Section
Special Emphasis Panel (ZRG4-GMB (04))
Project Start
1987-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041367053
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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