Effect of hypoxic hepatocytes on normoxic proximal tubular cells on microfluidic devices

Although hepatocytes require a high amount of oxygen, the liver is a lobule structure with an oxygen gradient by blood flowing into the central vein. The part with the lowest oxygen partial pressure is characterized by a fairly low oxygen level. Thus, the liver is vulnerable to hypoxic environments, such as hypoxemia or low perfusion, leading to hypoxic hepatitis. Several studies have shown that hypoxic hepatitis is associated with kidney disease, aggravating kidney disease. Therefore, developing an in vitro model to examine the liver–kidney interactions under hypoxic conditions is very important. This study designed a microfluidic platform in which hepatocytes and kidney cells are connected in series. In this device, an oxygen-scavenging line with a flowing mixture solution of sodium sulfite and cobalt chloride was installed to remove oxygen only around the hepatocytes. A platinum octaethylporphyrin film was used to monitor the oxygen concentrations in the device. The oxygen partial pressure dropped to approximately 3% through this device. The cytotoxicity of hypoxic hepatocytes assessed by the LDH assay was up to 7.6 times higher than that of the control. Hepatocytes exposed to hypoxia tended to increase glucose uptake rates and glycogen synthesis. In the microfluidic device, the injury markers of the kidney cells also increased when only the hepatocytes were exposed to a hypoxic environment. Abnormal glycogen accumulation in hypoxic hepatocytes can increase cytotoxicity in normoxic kidney cells. In this study, we confirmed that the liver exposed to hypoxic environment in vitro can affect the normal kidney through abnormal glycogen accumulation in the microfluidic devices.