Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression

Tarek Ashkar (El-Achkar), Xue Ru Wu, Michael Rauchman, Ruth McCracken, Susan Kiefer, Pierre Dagher

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Tamm-Horsfall protein (THP) is a glycoprotein with unclear functions expressed exclusively in thick ascending limbs (TAL) of the kidney. Its role in ischemic acute kidney injury is uncertain, with previous data suggesting a possible negative effect by enhancing cast formation and promoting inflammation. Using a recently characterized THP knockout mouse (THP-/-), we investigated the role of THP in renal ischemia-reperfusion injury (IRI). In wild-type mice (THP+/+), THP expression was increased by injury. THP-/- mice developed more functional and histological renal damage after IRI compared with THP+/+. THP-/- kidneys showed more inflammation and tubular necrosis. Cast formation correlated with the severity of injury and was independent of THP presence. THP absence was associated with a more necrotic, rather than apoptotic, phenotype of cell death. The outer medulla was predominantly affected, where significant interstitial neutrophil infiltration was detected in proximity to injured S3 proximal tubular segments and TAL. This coincided with an enhanced expression of the innate immunity receptor Toll-like receptor 4 (TLR4) in S3 segments of THP-/- compared with THP+/+ mice. Specifically, a basolateral S3 expression of TLR4 was more evident in THP-/- kidneys compared with a more apical distribution in THP+/+. Such basolateral location for TLR4 allows a greater interaction with proinflammatory ligands present in the interstitium during ischemia. In conclusion, we are showing a completely novel role for a very old protein in the setting of renal injury. Our data suggest that THP stabilizes the outer medulla in the face of injury by decreasing inflammation, possibly through an effect on TLR4.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number2
DOIs
StatePublished - Aug 2008

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Uromodulin
Toll-Like Receptor 4
Inflammation
Kidney
Wounds and Injuries
Reperfusion Injury
Extremities

Keywords

  • Acute kidney injury
  • Ischemia-reperfusion
  • Toll-like receptors
  • Uromodulin

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. / Ashkar (El-Achkar), Tarek; Wu, Xue Ru; Rauchman, Michael; McCracken, Ruth; Kiefer, Susan; Dagher, Pierre.

In: American Journal of Physiology - Renal Physiology, Vol. 295, No. 2, 08.2008.

Research output: Contribution to journalArticle

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AB - Tamm-Horsfall protein (THP) is a glycoprotein with unclear functions expressed exclusively in thick ascending limbs (TAL) of the kidney. Its role in ischemic acute kidney injury is uncertain, with previous data suggesting a possible negative effect by enhancing cast formation and promoting inflammation. Using a recently characterized THP knockout mouse (THP-/-), we investigated the role of THP in renal ischemia-reperfusion injury (IRI). In wild-type mice (THP+/+), THP expression was increased by injury. THP-/- mice developed more functional and histological renal damage after IRI compared with THP+/+. THP-/- kidneys showed more inflammation and tubular necrosis. Cast formation correlated with the severity of injury and was independent of THP presence. THP absence was associated with a more necrotic, rather than apoptotic, phenotype of cell death. The outer medulla was predominantly affected, where significant interstitial neutrophil infiltration was detected in proximity to injured S3 proximal tubular segments and TAL. This coincided with an enhanced expression of the innate immunity receptor Toll-like receptor 4 (TLR4) in S3 segments of THP-/- compared with THP+/+ mice. Specifically, a basolateral S3 expression of TLR4 was more evident in THP-/- kidneys compared with a more apical distribution in THP+/+. Such basolateral location for TLR4 allows a greater interaction with proinflammatory ligands present in the interstitium during ischemia. In conclusion, we are showing a completely novel role for a very old protein in the setting of renal injury. Our data suggest that THP stabilizes the outer medulla in the face of injury by decreasing inflammation, possibly through an effect on TLR4.

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