Abstract
Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.
Highlights
Uromodulin (UMOD), known as Tamm-Horsfall protein (THP), is a glycoprotein with a molecular weight of 80-90kDa expressed by epithelial cells lining the thick ascending limb (TAL) of the loop of Henle and to minor degree the early distal convoluted tubules [1, 2]
UMOD is a pleiotropic protein secreted by tubular epithelial cells of the thick ascending limb of the loop of Henle and to a lesser degree the early distal convoluted tubule
We investigated a potential proinflammatory role of extratubular UMOD using pUMOD isolated from human urine
Summary
Uromodulin (UMOD), known as Tamm-Horsfall protein (THP), is a glycoprotein with a molecular weight of 80-90kDa expressed by epithelial cells lining the thick ascending limb (TAL) of the loop of Henle and to minor degree the early distal convoluted tubules [1, 2]. In mouse models of unilateral ureteral obstruction (UUO) accompanied with an inflammatory response, pUMOD accumulation, and extratubular deposition have been documented [28,29,30]. These findings imply a potential proinflammatory role of pUMOD under pathological conditions. We identified an upregulation and abnormal localization of UMOD accompanied by leukocyte infiltration in the mouse model of neonatal obstructive nephropathy and in renal biopsies from patients with various chronic renal inflammatory disorders. Our study expands the current knowledge of the broad spectrum of UMOD functions, supporting the proinflammatory and damage associated molecular pattern (DAMP)-like role of extratubular pUMOD in kidney pathologies
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