Pharmacological antagonism of HTR2B reduces ERK and STAT3 activation and prevents renal fibrosis during the development of Adenine-Induced CKD in rats.

Chronic kidney disease (CKD) is a debilitating condition affecting roughly 1 in 7 people in the United States. CKD is characterized by loss of renal function due to nephron loss and fibrosis. MARY1 is a novel 5-hydroxytryptamine 2B receptor (HTR2B) antagonist that stimulates mitochondrial biogenesis and augments recovery after ischemia/reperfusion-induced acute kidney injury (AKI) in vivo. We evaluated the potential of MARY1 to prevent CKD development in an adenine-induced rat model. Rats were given a normal diet or a diet supplemented with 0.2% adenine for 4 weeks to induce CKD. Adenine-fed rats were simultaneously administered either MARY1 (0.15 mg/kg, IP) or vehicle daily throughout the 4 weeks. Adenine diet resulted in renal cortical fibrosis and upregulation of two kidney damage markers: kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), consistent with CKD development. MARY1 mitigated the induction of KIM-1 and NGAL by 52% and 68%, respectively. Nicotinamide adenine dinucleotide (NAD + ) was reduced by 69% in vehicle-treated adenine-exposed rats, which was prevented by MARY1. Adenine increased activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3), resulting in increased expression of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). MARY1 reduced activation of ERK and STAT3, and mitigated NF-κB upregulation by 64%. MARY1 also attenuated adenine-induced fibrosis in the renal cortex by 43%. These findings support HTR2B antagonism as a novel strategy for preventing CKD-associated mitochondrial dysfunction, renal inflammation, and fibrosis during disease development.