The novel potential therapeutic target PSMP/MSMP promotes acute kidney injury via CCR2.

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.

Down-regulating insulin-like growth factor-1 receptor reduces amyloid-ß deposition in mice cortex induced by chronic sleep restriction.

OBJECTIVE: Insufficient sleep affects cognitive function, but the underlying mechanism and potential protective ways are yet to be fully understood. This study aimed to explore the influence of chronic sleep restriction (CSR) on the insulin-like growth factor-1 (IGF-1) signaling pathway, and whether down-regulating IGF-1 signaling pathway would modulate amyloid-ß (Aß) peptides metabolism and its cortical deposition after CSR. Methods 8-week IGF-1R+/- mice and wild-type (WT) C57BL/6 (C57) mice were divided into four groups: IGF-1R+/- CSR (MUSR), IGF-1R+/- control (MUCO), C57 CSR (C57SR) and C57 control (C57CO). CSR model was established by application of slowly rotating drum for 2 months. Body weight and Lee's index were measured. The level of IGF-1 in plasma was measured by enzyme linked immunosorbent assay (ELISA). Aß accumulation was detected by immunofluorescence. The expressions of amyloid precursor protein (APP), ß-site amyloid precursor protein-cleaving enzyme-1 (BACE-1) and C99 were detected using western-blot (WB). Results Two-way ANOVA showed genotypic effect was significant on body weight and Lee's index. Neither treatment effect nor interaction reached significant difference on body weight and Lee's index. The level of IGF-1 in plasma was significantly decreased in C57SR compared with C57CO. Besides, compared with C57CO, Aß was markedly accumulated in frontal cortex, in parallel with increased expressions of BACE-1 and C99, and with no difference of APP in C57SR group. Further, no significant changes of Aß, BACE-1, C99 and APP were detected in MUSR compared with MUCO. Conclusions This study showed that CSR could induce the decrease of circulating IGF-1 in mice. By using the IGF-1R+/- mice, we found that down-regulating IGF-1R could reduce Aß deposition in mice frontal cortex after CSR via inhibiting BACE-1 protein expression and activity, which were independent of the changes of body weight and Lee's index. These findings indicate that the blockage of IGF-1 signaling pathway might be a protection mechanism for alleviating the impact of CSR.