HTR1F Is Essential for Renal Recovery After Acute Kidney Injury

Kidney disease is a growing global health crisis, affecting 1 in 7 adults in the United States and becoming one of the leading causes of morbidity and mortality worldwide. Kidney disease can result from conditions such as high blood pressure, type 1 or type 2 diabetes, prolonged urinary tract obstruction, and other underlying causes. Common symptoms include nausea, loss of appetite, fatigue, and weakness, though these symptoms often become more severe as the disease progresses. Kidney disease acts to compromise the structural and/or functional integrity of the kidney. Identification of therapeutic agents that can effectively treat or blunt the onset or progression of kidney disease remains of vital importance. Previous research has shown that the 5-hydroxytryptamine 1F receptor (HTR1F) can modulate renal mitochondrial homeostasis and mice lacking this receptor took longer to recover from induced acute kidney injury (AKI). The goal of this study was to further investigate the role of HTR1F in kidney recovery after moderate to severe AKI. This study also evaluated whether lasmiditan, a U.S. Food & Drug Administration (FDA)-approved medication for the treatment of acute migraines that activates HTR1F, can aid in kidney recovery after injury. The results showed that mice lacking HTR1F had a ~30% higher mortality rate after moderate to severe AKI. Mice that already had HTR1F that were treated with lasmiditan exhibited a faster recovery of kidney function and reduced tubular injury and fibrosis. Overall, these findings highlight HTR1F as a critical regulator of kidney recovery and lasmiditan as a promising therapeutic target with beneficial effects through its activation of HTR1F. 

What were the methods of data collection and analysis? 

The researchers used a mouse model of moderate to severe AKI induced by ischemia/reperfusion (temporary loss and restoration of blood flow) to study the role of HTR1F and the effects of lasmiditan treatment.  Both wild-type mice, or un-altered mice, and genetically engineered mice with a whole-body deletion of the HTR1F gene were included to determine receptor-specific effects. Mice were treated daily with either lasmiditan, an HTR1F activator, or a control beginning 24 hours after injury. Kidney function was assessed by measuring serum creatinine levels at 24 hours, 7 days, and 14 days post-injury. Serum creatinine is a blood test that assesses kidney function by measuring creatinine, a muscle waste product filtered out through the kidneys.  

Gene expression was measured using quantitative real-time PCR, while protein levels of key markers such as KIM1, nGAL, and PGC-1α,were measured by Western Blotting for markers of kidney injury, mitochondrial biogenesis, and fibrosis. The kidney is one of the most metabolically active organs in the human body, requiring a significant amount of energy in the form of adenosine 5’-triphosphate (ATP) to function properly. Since mitochondria are responsible for producing the majority of cellular ATP, measuring the production of mitochondria in the cell provides important insight into kidney recovery and function after injury. Histological evaluation (microscopic examination of tissue to study structure and understand biological processes) was used to assess tubular damage, fibrosis (buildup of scar tissue), and renal vascular density. Histological evaluation was assessed using a 5-point scale, with 0 indicating no tubular injury, 1: 1%-10% tubular injury, 2: 11%-25% tubular injury, 3: 26%-50% tubular injury, 4: 51%-75% tubular injury, and 5: >75% tubular injury.  

What were the results of this study? 

This study found that mice lacking HTR1F experienced significantly worse outcomes following moderate to severe AKI compared to the control group. These outcomes included a ~30% increase in mortality, greater kidney damage, reduced mitochondrial function, increased fibrosis, and more severe loss of renal blood vessels. In contrast, mice with normal HTR1F levels showed improved kidney recovery when treated with lasmiditan, as evidenced by reduced serum creatinine levels, less tubular injury, decreased fibrosis, preserved mitochondrial biogenesis, and reduced vascular rarefaction. Importantly, in mice lacking HTR1F, lasmiditan had no beneficial effects on kidney recovery, demonstrating that lasmiditan cannot act to preserve and restore kidney function without HTR1F.   

Kidney injury molecule-1 (KIM1) is a dormant protein that is expressed following injury to the proximal tubule cells within the renal cortex and neutrophil gelatinase-associated lipocalin (nGAL) is an early biomarker protein of AKI released by renal cells following the onset of injury. Elevated KIM1 and nGAL levels were observed in the kidney at all timepoints post AKI, regardless of what kind of mouse or treatment, which indicates renal injury. In addition, mice treated with lasmiditan displayed reduced KIM1 protein (46%) and nGAL levels (40%), as well as for mice with normal HTR1F production without lasmiditan treatment, with a ~35% reduction in KIM1 levels. Peroxisome proliferator-activated receptor Gamma coactivator 1-alpha (PGC-1α), a major regulator of mitochondria production, decreased 24 hours after injury in both mice with and without HTR1F expression. Partial kidney restoration was observed 14 days after injury, with PGC-1α levels increasing in both mice with and without HTR1F expression, by 44% and 69%, respectively. Similarly, PGC-1α increased by 1.6-fold in mice treated with lasmiditan. Each of these changes in protein biomarker levels reflects the beneficial effects of HTR1F in combination with lasmiditan on kidney recovery.  

For histological evaluation, mice expressing and lacking HTR1F both had acute tubular injury scores of ~2 24 hours after injury, indicative of 11%-25% tubular injury. The control group of mice expressing and lacking HTR1F had a score of 2.57 and 2.25, respectively, indicative of >30% tubular injury. However, tubular injury scores decreased 43% between 7 days and 14 days in the control group and 41% for lasmiditan treated mice expressing HTR1F.  

What does this study indicate about our own health? 

This study highlights the importance of identifying effective therapeutic agents that support kidney health and recovery after injury. By identifying HTR1F as a key regulator of kidney repair, this research deepens our understanding of the molecular pathways involved in kidney recovery. These findings show that loss of HTR1F worsens kidney damage, disrupts renal blood vessel integrity, impairs mitochondrial function, and increases mortality. These findings emphasize the receptor’s essential role in maintaining normal kidney structure and function. Mice with normal HTR1F production showed significantly better kidney recovery and function, even after injury. Recovery from AKI depends heavily on mitochondrial health, vascular integrity, and proper repair of renal tubular cells, so the production of HTR1F is especially important to activate these processes.  

This study also explores lasmiditan as an activator of HTR1F and demonstrates that it significantly improves kidney recovery following moderate to severe AKI. Kidney disease and AKI remain major clinical challenges due to the complexity of the kidney and the limited availability of FDA-approved treatments. Thus, the identification of lasmiditan as a treatment for AKI and/or kidney disease onset/progression is particularly crucial to combat these issues. These findings also suggest that early treatment targeting HTR1F following kidney injury may help limit long-term damage and slow disease progression. Overall, these findings highlight lasmiditan as a promising therapeutic agent and confirm that its beneficial effects on renal recovery depend on HTR1F activation, reinforcing the receptor’s potential as a valuable target for future kidney disease treatments.