RELAXIN RECEPTOR, RXFP1, INITIATES ERK1/2 SIGNALING IN HUMAN CYSTIC KIDNEY EPITHELIAL CELLS
Alexis Trujillo1, Heather Ward2.
1The University of New Mexico, Albuquerque, NM, 2University of New Mexico Health Sciences Center, Albuquerque, NM.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder classified by cyst growth on kidney nephrons and collecting ducts. ADPKD is caused by mutation of PKD1 or PKD2, which encode polycystin-1 or -2, respectively. When mutant, polycystins induce aberrant signaling and perturb cellular polarity, which leads to cyst formation. Previously, our group demonstrated that relaxin-H2, an anti-fibrotic and vasodilatory hormone, decreases epithelial cell proliferation and slows cyst growth in a rodent model of ADPKD. We also established that expression of the relaxin-H2 receptor, RXFP1, is greatly up-regulated in human cyst-derived renal epithelial cells. In mesenchymal fibroblasts, RXFP1 initiates a signaling cascade through phosphorylation of ERK1/2 to intercept pathogenic TGF-Beta-1-mediated signaling. However, the epithelial RXFP1 signaling pathway remains to be defined. Therefore, we tested the hypothesis that relaxin-H2 signals through the ERK1/2 pathway in mesenchymal-like cystic epithelial cells. We treated normal and ADPKD human renal epithelial cells with relaxin-H2 and evaluated time-dependent phosphorylation of ERK1/2 via immunoblot. In ADPKD cells, maximal phosphorylation of ERK1/2 occurred between 10 and 15 minutes after addition of relaxin-H2 ligand, whereas normal epithelial cells exhibited minimal response. Our findings indicate that the early signaling events downstream of RXFP1 are conserved between fibroblasts and ADPKD renal epithelial cells and suggest that relaxin-H2 imparts a direct effect on human cystic epithelia. Thus, the RXFP1 signaling pathway may serve as a targetable mechanism to inhibit cyst growth in ADPKD.