DPP-4 Inhibitor Improved Social Behavior in Acute Kidney Injury in a Murine Model: Possible Role in Mitochondrial Functions

Abstract

Background: Kidney disease is usually complicated by multiple organ dysfunctions, such as cognitive impairment and neuropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors decrease the degradation of glucagon-like peptide-1 (GLP-1), improving glycemic control. This study investigated the effect of acute kidney injury (AKI) on social interaction and investigated the underlying role of inflammation, altered energetics, and the possible mode of action of a DPP-4 inhibitor on the brain in AKI. Methods: Forty rats constituted the animal model and were distributed into four groups (control, untreated, and treated AKI groups). We evaluated sociability; social novelty preferences in a three-chamber social apparatus; platelet counts; hippocampal mitochondrial enzyme complex (I–V) content by calorimetric methods; serum urea, blood urea nitrogen (BUN), and creatine phosphokinase levels by enzyme-linked immunoassay (ELISA); hippocampal adenosine triphosphate (ATP) content measured by ELISA; hippocampal glial fibrillary acidic protein (GFAP) expression; activity-regulated cytoskeleton-associated protein (Arc); Toll-like receptor 4 (TLR4) expression; and nuclear factor kappa B (NF-κB) expression by real-time polymerase chain reaction (RT‒PCR). Results: The sociability and social novelty indices, all hippocampal mitochondrial complexes (I to V), and platelet, ATP content, were significantly (p value ≤ 0.05) lower in the AKI group than in the control group. Serum creatinine, BUN, and creatine phosphokinase (CPK) levels, the relative expression of hippocampal GFAP, Arc, TLR4, and NF-κB were significantly (p value ≤ 0.05) increased in the AKI control group compared to those in the control group. Sections from the hippocampal cornu ammonis (CA) 1 (CA1) and 3 (CA3) regions and CA3 regions showed degeneration of pyramidal cells with microglial cell in filtration and the appearance of congested blood capillaries. Vildagliptin exerted a protective effect on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. The statistical significance was stated in parallel with intergroup variability. Conclusions: The present study showed the protective effect of vildagliptin on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. This improvement was attributed to improved mitochondrial function, which positively affects the energetics of the brain, attenuates the inflammatory response and alters the expression of synaptic proteins.