Abstract
KEY POINTS: Engineered Neuromedin U (LIMM102) had augmented efficacy in activating renal type 2 innate lymphoid cells (ILC2) both in vitro and in vivo. LIMM102 reduced mortality and enhanced kidney function in a model of AKI by activating renal ILC2s. The renoprotective effects of LIMM102 were neuromedin U receptor 1–dependent, highlighting the ILC2-neuromedin U receptor 1 axis as a novel therapeutic target for AKI therapy. BACKGROUND: AKI is a severe condition leading to the sudden loss of kidney function. Activation of type 2 innate lymphoid cells (ILC2s) by neuromedin U (NMU) is highly selective and key in controlling mucosal tissue repair and homeostasis. Renal ILC2s are associated with renoprotective effects in AKI. Here, we explored the therapeutic potential of an engineered NMU analogue (LIMM102) in a preclinical model of renal ischemia-reperfusion injury (IRI)–induced AKI. METHODS: LIMM102 was administered prophylactically to wild-type mice subjected to IRI-induced AKI and to Sham-operated controls. Survival, GFR, kidney function biomarkers, histopathologic analysis, and immune cell infiltration were assessed to determine LIMM102 treatment efficacy. Moreover, to interrogate the molecular selectivity of LIMM102, NMU receptor 1 (NMUR1)–deficient mice (Nmur1(−/−)) were used to formally test the need of NMUR1 signaling for the beneficial effects of LIMM102. RESULTS: LIMM102-treated IRI animals presented lower mortality rates when compared with their untreated IRI counterparts. Notably, LIMM102-treated animals displayed higher GFR, lower levels of kidney function biomarkers, and lower severity of kidney lesions, which associated with renal ILC2-activated phenotypes. Importantly, LIMM102 therapeutic effects relied entirely on NMUR1 signaling, as LIMM102 administration produced no beneficial effect on AKI outcome in Nmur1-deficient animals. CONCLUSIONS: LIMM102 exerted its therapeutic action by improving kidney function in IRI-induced AKI via NMUR1, which was associated with the presence of activated ILC2s in the kidney.