Tamm-Horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury

Tarek M. El-Achkar, Ruth Mccracken, Yan Liu, Monique R. Heitmeier, Soline Bourgeois, Jan Ryerse, Xue Ru Wu

Research output: Contribution to journalArticle

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Abstract

Tamm-Horsfall protein (THP) is a glycoprotein normally targeted to the apical membrane domain of the kidney's thick ascending limbs (TAL). We previously showed that THP of TAL confers protection to proximal tubules against acute kidney injury (AKI) via a possible cross talk between the two functionally distinct tubular segments. However, the extent, timing, specificity, and functional effects of basolateral translocation of THP during AKI remain unclear. Using an ischemia-reperfusion (IRI) model of murine AKI, we show here that, while THP expression in TAL is downregulated at the peak of injury, it is significantly upregulated 48 h after IRI. Confocal immunofluorescence and immu-noelectron microscopy reveal a major redirection of THP during recovery from the apical membrane domain of TAL towards the basolateral domain, interstitium, and basal compartment of S3 segments. This corresponds with increased THP in the serum but not in the urine. The overall epithelial polarity of TAL cells does not change, as evidenced by correct apical targeting of Na+-K+-2Cl cotransporter (NKCC2) and basolateral targeting of Na+-K+-ATPase. Compared with the wild-type, THP~/~ mice show a significantly delayed renal recovery after IRI, due possibly to reduced suppression by THP of proinflammatory cytokines and chemokines such as monocyte che-moattractant protein-1 during recovery. Taken together, our data suggest that THP redistribution in the TAL after AKI is a protein-specific event and its increased interstitial presence negatively regulates the evolving inflammatory signaling in neighboring proximal tubules, thereby enhancing kidney recovery. The increase of serum THP may be used as a prognostic biomarker for recovery from AKI.

Original languageEnglish (US)
Pages (from-to)1066-1075
Number of pages10
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number8
DOIs
StatePublished - Jun 11 2013

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Keywords

  • Kidney injury
  • Tubular cross talk
  • Uromodulin

ASJC Scopus subject areas

  • Physiology
  • Urology

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