Diminished Motor Response to d-Amphetamine in Tamm-Horsfall Protein (THP) Knockout Mice

Background: THP is a kidney-derived protein secreted into urine and blood. Its circulating form inhibits oxidative stress in the kidney, circulation, and distant organs. THP is protective in acute kidney injury (AKI) and its levels are decreased in AKI and chronic kidney disease (CKD). AKI and CKD are risk factors for various neurological conditions. We are interested in its potential protective role in the Central Nervous System (CNS), since the ion channel mediating THP’s antioxidant effects (TRPM2) is expressed in dopaminergic (DA) neurons. Prior studies identified THP-positive cells in the rat CNS and human cerebral spinal fluid, suggesting THP’s presence in the CNS, though its interaction with neuronal populations remains unclear. Since DA neurons are crucial for motor control, we investigated how THP impacts motor function with and without stimulation of DA activity. Methods: In collaboration with the IU Behavioral Phenotyping Core, we conducted exploratory locomotor activity assessments on twelve male and female mice per genotype (THP+/+, THP+/- and THP-/-), followed by measurement of food, water and fructose consumption and motor activity in a metabolic cage. Mice then received escalating doses of d-Amphetamine (d-AMP, up to 10 mg/kg) to activate DA signaling, with movement time and distance measured after each dose. Brain, spinal cord, kidneys, and serum were collected following phenotyping. Results: THP-/- mice showed no differences in grip strength, wheel rotations, or rotarod performance compared to THP+/+ or THP+/- controls. Metabolic cage measurements recapitulated findings that THP-/- mice drink more water than control animals and showed a variable preference of THP-/- mice for fructose. THP-/- mice exhibited reduced movement following a 3 mg/kg dose of d-AMP, with a more pronounced effect in females. This stunted response to d-AMP persisted in fructose-naïve mice, indicating it was not due to testing stress. Conclusion: Since d-AMP leads to increased DA signaling in the brain, reduced movement following d-AMP administration suggests a role for systemic THP in midbrain DA neuronal maintenance. This is consistent earlier findings that THP crosses the blood-brain barrier (BBB) and the expression of TRPM2 in DA neurons. Future studies will examine THP’s interactions with DA neurons in health and injury models and clarify the mechanisms underlying its BBB passage. Funding: NIDDK Support