MP080
UROMODULIN EXERTS POTENT PREVENTIVE AND THERAPEUTIC EFFECTS IN WKY RATS WITH ANTIGBM GLOMERULONEPHRITIS VIA IL6 ACTIVATION Free

Introduction and Aims: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. Although several reports have described the anti-inflammatory and immunomodulatory effects of UMOD, the effects on the kidney diseases remains unclear. In this study, the therapeutic effects of UMOD and its mechanism were examined in nephrotoxic serum nephritis (NTS-N) of Wistar Kyoto (WKY) rats.

Methods: NTS-N was induced in WKY rats on day 0. In the preventive study, the groups of animals were administered either UMOD (WKY-UMOD) or vehicle (WKY-CON) just before NTS administration, then the rats were sacrificed on Day 4. In the therapeutic study, the treatment was started on Day 4, then the rats were sacrificed on Day 10. In vitro, the potential role of UMOD in the induction of cytokines in HUVECs and human mesangial cells (NHMCs) was evaluated.

Results: We found that UMOD exerted potent preventive and therapeutic effects on NTS-N both functionally and histologically. In the preventive study on Day 4, UMOD treatment dramatically reduced proteinuria in NTS-N to the level of rats without nephritis (WKY-CON vs. WKY-UMOD, 63.65 ± 10.90 vs. 21.17 ± 5.81 mg/day, p < 0.01), and significantly inhibited renal dysfunction (serum creatinine (Cr) level: p < 0.01). Histologically, UMOD-treated rats had significantly reduced crescent formation (% crescentic glomeruli: 59.0 ± 1.86 vs. 34.83 ± 1.95 %, p < 0.001), fibrin deposition (p < 0.001), glomerular ED1+ macrophages accumulation (p < 0.001), the number of CD8+ cells per glomerular cross-section (GCS) (p < 0.05), and the number of TUNEL+ apoptotic cells per GCS (p < 0.001). In the therapeutic study on Day 10, UMOD treatment significantly reversed proteinuria (74.34 ± 5.60 vs. 50.61 ± 3.34 mg/day, p < 0.01) and ameliorated renal histological findings (% crescentic glomeruli: p < 0.001), but no significant reduction of the serum Cr level was observed. To investigate the therapeutic mechanism of UMOD, we evaluated the cytokines profile in very early phase of NTS-N. After 3 hours of UMOD treatment, the serum IL-6 level (11.18 ± 6.17 vs. 1154.91 ± 726.85 pg/ml, p < 0.05) but not other cytokines and IL-6 mRNA expression level in renal cortex (1.62 ± 0.37 vs. 37.03 ± 14.44, p < 0.05) were dramatically increased. Significantly reduced glomerular ED1+ macrophages accumulation was also seen. In vitro, UMOD stimulation of HUVECs and NHMCs led to a dose-dependent increase in IL-6 release, which were augmented by TNF-α co-stimulation.

Conclusions: The present results showed that UMOD dramatically ameliorated experimental anti-GBM glomerulonephritis via anti-inflammatory effects possibly by increasing systemic and renal IL-6 production.