5-HT1F Agonist Lasmiditan Induces Mitochondrial Biogenesis And Alters Successful And Failed Repair Genes In A Mouse Model Of Acute Kidney Injury

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<b>Abstract ID 24411</b> <b>Poster Board 501</b> <b>Background:</b> AKI is defined as an onset and progressive decline in renal function and is often accompanied by a persistent reduction in mitochondrial function, fatty acid oxidation and vascular injury. AKI is an important public health concern with no FDA-approved treatments. We have shown that FDA approved 5-HT1F receptor agonist lasmiditan stimulates mitochondrial biogenesis (MB) and accelerates renal recovery in a mouse model of AKI. <i>Kirita et&nbsp;al</i>,2020 recently performed single nucleus sequencing in mouse AKI and reported conserved cellular responses and profiled successful and failed repair genes. We sought to explore the role of lasmiditan on selective successful and failed repair genes post-AKI in our AKI model system. <b>Methods:</b> Male 8-week-old C57B/6J mice were administered 0.3mg/kg of lasmiditan or normal saline 24h after I/R and then every 24h over a 144h period (n=6/group). Kidneys were harvested and snap frozen in liquid nitrogen. Renal cortex samples were used to analyze gene expression (qRT-PCR) and protein expression (immunoblot) post AKI. One way ANOVA followed by TUKEY multiple comparison test was used to determine statistical significance between treatment groups. A p-value of p≤0.05 were used to identify statistical changes and correct for multiple comparisons<b>.</b> <b>Results:</b> Serum creatinine and Kidney injury marker 1 <i>(KIM1)</i> was measured and found to be maximally elevated at 24h post I/R and lasmiditan treated groups decreased serum creatine (∼4 fold) and <i>KIM1</i>(∼2.7fold) over time compared to vehicle and IR24. qRT-PCR analysis revealed increase of successful repair genes – <i>ACSM2a, LRP2</i>, <i>SLC5A12</i> and <i>HNF4A</i> upon lasmiditan treatment and failed repair genes – <i>VCAM, LCN2</i>, <i>RELB</i> and <i>KCNIP4</i> in 144h of lasmiditan treatment. At 24h and I/R vehicle, mRNA levels of successful repair genes in IR24 decreased and increased in at 144h of lasmiditan treatment. Alternatively, mRNA levels of failed repair genes were elevated at IR24 and lasmiditan treatment did not reduce the expression of failed markers to sham levels. These findings were confirmed using immunoblot analysis. <b>Conclusion:</b> These data affirm the role of 5-HT1F agonist Lasmiditan mediating the transcriptional and translational level of successful and failed repair genes thus contributing to fatty acid metabolism, reabsorption of lactate and inflammation but the molecular mechanism is still unclear. This approach will allow us to identify and assess key genes responsible for pathophysiological changes during AKI and other kidney diseases, and the effects of drugs stimulating repair/recovery. This work was supported by grant: BX000851 (Department of Veterans Affairs) to RGS.