Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

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.

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation

“…β 2 Integrin activation assay was performed as previously described. 21 Briefly, PAP-1 (10 nM) or vehicle pre-incubated isolated human neutrophils were stimulated with CXCL8 (10 nM) in the presence of either mouse-α-human KIM127 (InVivo, 10 µg µL −1 ) or mouse α-human mAB24 (Hycult Biotech, 10 µg µL −1 ) antibody for 5 min at 37°C in HBSS. Stimulation was stopped by adding ice-cold FACS lysing solution (BD BioScience).…”

The Effect of miR-505-5p on Inhibition of Serum Uromodulin Ameliorates Myocardial Inflammation and Apoptosis Induced by Ischemia-Reperfusion

“…sUmod was reported to interact with myoloid dendritic cells (DCs), monocytes, and neutrophils through toll-like receptor 4 (TLR4), and has an effect on the regulation of inflammation as well as innate immunity [ 30 ], and the immunosuppressive effect of sUmod was achieved by binding to TNF- α and interleukin-1 [ 31 ]. In addition, sUmod stimulated extrarenal tissue, and caused strong inflammatory response, which was characterized by obviously recruiting inflammatory monocytes and neutrophils [ 32 ]. sUmod induced the secretion of TNF- α and the expression of tissue factors in human monocytes, triggered DC maturation through activating NF- κ B and TLR4, and activated protease release, respiratory burst, degranulation, and phagocytosis of neutrophils [ 33 ].…”

The genetic communication and interaction between chronic kidney diseases and frailty

“…30 The dysregulation of UMOD expression can result in infiltration of peritubal leukocyte in the kidneys and consequently cause kidney inflammation, which has a strong correlation with the development of frailty. 31 Diabetic kidney disease (DKD) and hypertensive kidney disease (HKD) are prevalent forms of CKD, which are linked to the heredity of the kidneys and the decline in kidney function. Many clinical studies revealed that both DKD and HKD are correlated with an elevated risk of frailty.…”

“…reported that UMOD is highly heritable and encodes urinary regulatory protein (Tamm Horsfall protein) in the Henle ring region 30 . The dysregulation of UMOD expression can result in infiltration of peritubal leukocyte in the kidneys and consequently cause kidney inflammation, which has a strong correlation with the development of frailty 31 …”