5-Hydroxytryptamine 2B receptor antagonism restores ATP and reduces tubulointerstitial fibrosis in the renal cortices of aged mice

Age is a prominent risk factor for the development of kidney disease, emphasizing the importance of understanding and mitigating the mechanisms underlying renal aging. Aging mitochondria in tubular cells become increasingly dysfunctional, reducing ATP production, and increasing reactive oxygen species, which drives inflammation. Pharmacological induction of mitochondrial biogenesis, the generation of new and functional mitochondria, restores renal function in mouse models of kidney disease, including acute kidney injury and diabetic kidney disease. The potential of this therapy in age-related renal decline remains unknown. 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide (MARY1) is a novel, selective serotonin 2B receptor antagonist that induces mitochondrial biogenesis and improves recovery after acute kidney injury in vivo. Young (12-week-old) and aged (104-week-old) male mice were treated with MARY1 (0.3 mg/kg, i.p.) or vehicle daily for 3 weeks. Mice were euthanized at 15- and 107-weeks, respectively, and the kidneys collected for analyses. Aged 107-week-old mice exhibited increased phosphorylation of mammalian target of rapamycin, decreased AMP-activated protein kinase phosphorylation, decreased ATP, and increased inflammation and fibrosis in the renal cortex compared with young controls. MARY1 treatment restored AMP-activated protein kinase phosphorylation, and increased protein kinase B activity and ATP content. MARY1 decreased the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 and reduced markers of renal inflammation and fibrosis in the aged kidney, including vascular cell adhesion molecule 1, collagen-1, and collagen deposition. These findings suggest that MARY1 treatment restores mitochondrial metabolism and ameliorates age-related renal inflammation and fibrosis in mice, supporting its potential as a therapeutic strategy to preserve renal function during aging. SIGNIFICANCE STATEMENT: Age-related kidney dysfunction is driven in part by declining mitochondrial metabolism and chronic inflammation. This study reveals that the novel selective serotonin 2B receptor antagonist 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide restores mitochondrial metabolism and reduces renal inflammation and fibrosis in aged mice, supporting pharmacological induction of mitochondrial biogenesis and 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide as a promising strategy to preserve kidney function during aging.