P0710DUAL GPR40/GPR84 FATTY ACID RECEPTOR DELETION IMPROVES ADENINE-INDUCED RENAL INJURY IN MICE
NEPHROLOGY DIALYSIS TRANSPLANTATION(2020)
摘要
Abstract Background and Aims Fatty acid receptors have recently been implicated in the progression of fibrotic disorders. GPR40 deletion predisposes to AKI and CKD-induced fibrosis, while deletion of the pro-inflammatory GPR84 receptor was beneficial in this context. PBI-4050, a novel therapeutic compound with excellent safety and efficacy profiles in both experimental and clinical settings, is a dual GPR40 agonist and GPR84 antagonist. In this study, we sought to determine which of these receptors had a predominant effect in adenine-induced CKD. Method Ten-week-old male GPR40/84 double knockout mice (40/84ko) and age/strain matched WT C57BL/6 mice were subjected to a regular or adenine-supplemented diet (0.25%) for 4 weeks (n=10 per group). Plasma samples were collected on a weekly basis for hematocrit assessment. At endpoint, mice were placed in metabolic cages for 24 hours for urine collection. Plasma minerals and electrolytes, urinalysis and a comprehensive blood count were performed at endpoint. Results Adenine feeding led to early and sustained weight-loss, which was significantly worse in WT mice compared to 40/84ko mice. At day 14, Hct was significantly decreased in adenine-fed WT mice, while unaffected in the 40/84ko group. Adenine-induced reductions in hemoglobin and red blood cells counts were also greatly improved in 40/84ko mice. Adenine-feeding led to increased circulating neutrophils and decreased lymphocyte in WT mice, which was not seen in 40/84ko mice. Importantly, renal function assessed by plasma creatinine, urea and creatinine-clearance and renal hypertrophy were significantly improved in Ad-fed 40/84ko mice. Moreover, fractional excretion for sodium, potassium and calcium were increased by adenine-feeding in WT, but not in 40/84ko mice. Conclusion Overall, the loss of both GPR40 and GPR84 led to major improvements in several key renal functional abnormalities associated with adenine-induced CKD including weight-loss, anemia and renal functional decline. These studies, along with our previous work highlight the potential of targeting fatty-acid GPCR’s, notably GPR84, for the treatment of inflammation/fibrosis related kidney diseases.
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