Genetic deletion of neuromedin U and neuromedin S confers transient reno-protection in adenine-induced chronic kidney disease.

Abstract

Neuromedin U (NMU) and neuromedin S (NMS) are neuropeptides that regulate metabolic, inflammatory, and fibrotic responses through shared receptors. Although dysregulated NMU/NMS signaling has been implicated in metabolic and inflammatory disorders, its involvement in chronic kidney disease (CKD) is unknown. In this study, using an adenine-induced CKD model, we demonstrated that renal mRNA expression of NMU and its receptor NMUR1 was significantly upregulated in parallel with disease progression, suggesting a potential role for this signaling system in CKD pathophysiology. Based on this observation, we examined the impact of genetic deletion of NMU and NMS on adenine-induced renal injury, and demonstrate for the first time that loss of NMU/NMS signaling confers transient reno-protection in experimental CKD.　NMU/NMS double-knockout (dKO) and wild-type mice were fed a 0.2 % adenine diet for 2, 4, or 6 weeks. Renal atrophy and elevations in blood urea nitrogen progressed similarly in both groups; however, serum creatinine levels were significantly lower in dKO mice at 4 weeks, indicating partial preservation of renal function. Gene expression analyses revealed attenuated early inflammatory-fibrotic responses in dKO kidneys, including reduced Tgfb1 mRNA expression at 2 weeks and decreased F4/80 and Col1a1 expression at 4 weeks. Importantly, renal TGF-β1 protein levels were also significantly reduced in dKO mice at 2 weeks. Histological analysis demonstrated a marked reduction in interstitial fibrosis in dKO mice at 4 weeks, whereas no differences were observed at 6 weeks. Together, these findings identify NMU/NMS signaling as a previously unrecognized regulator of early injury responses in experimental CKD.