Cisplatin-induced acute kidney injury increased brain 5-HT levels partly due to the hippuric acid-induced upregulation of CYP2D4 expression and function in brain of rats

Patients with acute kidney injury (AKI) are often associated with uremic encephalopathy, but its underlying mechanisms remain unclear. This study aimed to investigate how AKI induced neuropsychiatric disorders through cerebral 5-hydroxytryptamine (5-HT) dysregulation in cisplatin-induced AKI rats. Our findings demonstrated that AKI induced anxiety-like behaviors and increased cerebral 5-HT levels, which may be attributed to the upregulated CYP2D4 expression and activity. The intraventricular injection of quinine (CYP2D4 inhibitor) attenuated the elevated cortical 5-HT levels in AKI rats. Intraperitoneal administration of 5-methoxytryptamine (CYP2D4 substrate) also provoked anxiety-like behaviors and cerebral 5-HT accumulation, which were reversed by cotreatment with quinine. Hippuric acid (HA), as a classical uremic toxin, was severely accumulated in both the plasma and brain of AKI rats. In vitro experiments demonstrated that HA-induced reactive oxygen species (ROS) upregulated expression of CYP2D6 (over 70% homology with rat CYP2D4) via suppressing Nrf2/HO-1 pathway in SH-SY5Y cells. These effects were reversed by ROS scavenger N-acetylcysteine, Nrf2 activator sulforaphane, and HO-1 activator cobalt-protoporphyrin IX. Similarly, either Nrf2 inhibitor ML385 or HO-1 inhibitor zinc-protoporphyrin IX exerted up-regulatory effects on CYP2D6 expression. In vivo studies confirmed that HA treatment induced AKI-like behavioral abnormalities in rats, accompanied by increased cerebral 5-HT levels and CYP2D4 expression as well as induced production of ROS, decreased Nrf2 and HO-1 protein levels. Our findings elaborate a novel mechanism between kidney failure and neuropsychiatric complications. Specifically, cisplatin-induced AKI upregulates CYP2D4 expression via HA-mediated ROS release, subsequently promoting generation of cerebral 5-HT by CYP2D4 and revealing material basis of AKI-associated uremic encephalopathy. SIGNIFICANCE STATEMENT: This study revealed that the psychiatric disorders of cisplatin-induced acute kidney injury rats are partly attributed to the increased 5-hydroxytryptamine levels induced by brain CYP2D. The induction of CYP2D4 is mainly due to brain accumulation of hippuric acid via inactivation of Nrf2/HO-1 pathway by reactive oxygen species.