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1 Medicine-Nephrology, Saint Louis University- St Louis VA Medical Center, Saint Louis, Missouri, United States
2 Urology, New York University School of Medicine, 550 First Avenue, New York, New York, 10016, United States; Pathology, New York University School of Medicine, New York, New York, United States
3 Medicine-Nephrology, Saint Louis University- St Louis VA Medical Center, Saint Louis, Missouri, United States; Biochemistry, Saint Louis University, St Louis, Missouri, United States
4 Medicine, Indiana university, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: tarek.elachkar{at}va.gov.
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 to 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 TLR4 in S3 segments of THP-/- compared to THP+/+. Specifically, a basolateral S3 expression of TLR4 was more evident in THP-/- kidneys compared to a more apical distribution in THP+/+. Such basolateral location for TLR4 allows a greater interaction with pro inflammatory 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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