Uromodulin and Inflammation in Neonatal Obstructive Nephropathy

• Applicant: Professorin Dr. Bärbel Lange-Sperandio
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421911754

Congenital obstructive nephropathy is the main cause of renal failure in infants and children. Renal insufficiency is due to impaired growth and maturation in the developing kidney with obstruction. Congenital obstructive nephropathy leads to tubular apoptosis, tubular atrophy, and interstitial fibrosis. Central to these events is the cytokine-mediated influx of macrophages into the obstructed kidney. Macrophages release chemokines, proinflammatory and profibrotic cytokines, and reactive oxygen species following unilateral ureteral obstruction. They activate fibroblasts and contribute to the development of tubulointerstitial injury. Uromodulin is a kidney-specific protein produced by cells of the thick ascending limb (TAL) of the loop of Henle. Uromodulin expression steadily increases with the maturation of the TAL segments, reaching a maximal level in fetal and neonatal life. The function of uromodulin under physiologic conditions is renoprotective. By contrast, under pathologic conditions uromodulin can activate inflammatory cells and trigger tubulointerstitial damage. This proinflammatory role of uromodulin seems to be mediated by monocytes and macrophages. Anti-inflammatory signaling pathways also influence the renal outcome after UUO. Interleukin-37 (IL-37) released by macrophages and tubular cells is natural inhibitor of inflammatory responses. Expression of IL-37 induces near complete suppression of proinflammatory cytokines. Interleukin-10 (IL-10) is another key immunosuppressive cytokine. IL-10 limits immune responses and protects from immune-mediated tissue damage and fibrosis. So far, uromodulin, IL-37, and IL-10 have not been studied for macrophage infiltration and tubulointerstitial injury following UUO in neonatal mice. Understanding the process of pro- and anti-inflammatory signaling in the neonatal kidney with obstruction will improve therapeutical strategies and help to limit the progression of renal insufficiency.

• DFG Programme: Research Grants