title: High-mobility group box 1 inhibits HCO(3)(-) absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway.
abstract: High-mobility group box 1 (HMGB1) is a damage-associated molecule implicated in mediating kidney dysfunction in sepsis and sterile inflammatory disorders. HMGB1 is a nuclear protein released extracellularly in response to infection or injury, where it interacts with Toll-like receptor 4 (TLR4) and other receptors to mediate inflammation. Previously, we demonstrated that LPS inhibits HCO(3)(-) absorption in the medullary thick ascending limb (MTAL) through a basolateral TLR4-ERK pathway (Watts BA III, George T, Sherwood ER, Good DW. Am J Physiol Cell Physiol 301: C1296-C1306, 2011). Here, we examined whether HMGB1 could inhibit HCO(3)(-) absorption through the same pathway. Adding HMGB1 to the bath decreased HCO(3)(-) absorption by 24% in isolated, perfused rat and mouse MTALs. In contrast to LPS, inhibition by HMGB1 was preserved in MTALs from TLR4(-/-) mice and was unaffected by ERK inhibitors. Inhibition by HMGB1 was eliminated by the receptor for advanced glycation end products (RAGE) antagonist FPS-ZM1 and by neutralizing anti-RAGE antibody. Confocal immunofluorescence showed expression of RAGE in the basolateral membrane domain. Inhibition of HCO(3)(-) absorption by HMGB1 through RAGE was additive to inhibition by LPS through TLR4 and to inhibition by Gram-positive bacterial molecules through TLR2. Bath amiloride, which selectively prevents inhibition of MTAL HCO(3)(-) absorption mediated through Na⁺/H⁺ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO(3)(-) absorption through a RAGE-dependent pathway distinct from TLR4-mediated inhibition by LPS. These studies provide new evidence that HMGB1-RAGE signaling acts directly to impair the transport function of renal tubules. They reveal a novel paradigm for sepsis-induced renal tubule dysfunction, whereby exogenous pathogen-associated molecules and endogenous damage-associated molecules act directly and independently to inhibit MTAL HCO(3)(-) absorption through different receptor signaling pathways.
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas dgood@utmb.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Good
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Thampi
authors.initials: T
authors.lastname: George
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Bruns A
authors.initials: BA
authors.lastname: Watts
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000494:pharmacology*; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000276:immunology; D018805:Sepsis / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C000593873:Ager protein, mouse; D001549:Benzamides; C572629:FPS-ZM1; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D008070:Lipopolysaccharides; D000067759:Receptor for Advanced Glycation End Products; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D017693:Sodium Bicarbonate
keywords: HMGB1; LPS-TLR4 signaling; RAGE; kidney; sepsis