High-mobility group box 1 inhibits HCO3 - absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway

David Good, Thampi George, Bruns Watts

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 HCO3 - 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 HCO3 - absorption through the same pathway. Adding HMGB1 to the bath decreased HCO3 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 HCO3 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 HCO3 - absorption mediated through Na+/H+ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO3 - 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 HCO3 - absorption through different receptor signaling pathways.

Original languageEnglish (US)
Pages (from-to)F720-F730
JournalAmerican Journal of Physiology - Renal Physiology
Volume309
Issue number8
DOIs
StatePublished - 2015

Fingerprint

Extremities
Toll-Like Receptor 4
Baths
Kidney
Sepsis
Sodium-Hydrogen Antiporter
MAP Kinase Signaling System
Amiloride
Nuclear Proteins
Advanced Glycosylation End Product-Specific Receptor
Fluorescent Antibody Technique
Inflammation
Membranes
Antibodies
Wounds and Injuries
Infection

Keywords

  • HMGB1
  • Kidney
  • LPS-TLR4 signaling
  • RAGE
  • Sepsis

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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title = "High-mobility group box 1 inhibits HCO3 - 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 HCO3 - 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 HCO3 - absorption through the same pathway. Adding HMGB1 to the bath decreased HCO3 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 HCO3 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 HCO3 - absorption mediated through Na+/H+ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO3 - 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 HCO3 - absorption through different receptor signaling pathways.",
keywords = "HMGB1, Kidney, LPS-TLR4 signaling, RAGE, Sepsis",
author = "David Good and Thampi George and Bruns Watts",
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T1 - High-mobility group box 1 inhibits HCO3 - absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway

AU - Good, David

AU - George, Thampi

AU - Watts, Bruns

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N2 - 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 HCO3 - 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 HCO3 - absorption through the same pathway. Adding HMGB1 to the bath decreased HCO3 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 HCO3 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 HCO3 - absorption mediated through Na+/H+ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO3 - 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 HCO3 - absorption through different receptor signaling pathways.

AB - 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 HCO3 - 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 HCO3 - absorption through the same pathway. Adding HMGB1 to the bath decreased HCO3 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 HCO3 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 HCO3 - absorption mediated through Na+/H+ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO3 - 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 HCO3 - absorption through different receptor signaling pathways.

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KW - Sepsis

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