Mechanism of kidney damage induced by chronic lead exposure in mice: Based on cyclic adenosine monophosphate/protein kinase A signaling pathway

Background Lead can cause kidney damage. It has been shown that cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway can mediate reactive oxygen species (ROS) overproduction by regulating the activity of oxidase and then cause oxidative stress and apoptosis. Nicotinamide adenine dinucleotide phosphate (NADPH) pathway is one of the main sources of ROS in kidney.

Objective This experiment investigates whether lead cause kidney damage by regulating the activity of NADPH oxidase 4 (NOX4) through cAMP/PKA pathway.

Methods Thirty SPF ICR mice were randomly divided into a control group and a lead exposure group, with 15 mice in each group. The animals were given free drinking water containing 0 and 200 mg·L^-1 lead acetate, respectively. After 90 days of continuous exposure, the mice were anesthetized to collect heart blood and kidney samples, weigh organs, and calculate organ coefficients. The lead levels in both blood and kidney were measured with graphite furnace atomic absorption spectrometer. Renal histomorphology was observed by HE staining and apoptosis was detected by TUNEL. The activities of total superoxide dismutase (T-SOD) and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and the levels of glutathione (GSH), malondialdehyde (MDA), and cAMP were detected using corresponding kits. The relative mRNA expression levels of PKA, NOX4, Bcl-2, Bax, and caspase3 were measured by quantitative real-time PCR.

Results There were no significant differences in body weight and daily water intake between the two groups. The renal coefficient(0.89±0.02)%, blood lead level(100.13±17.23) μg·L^-1, and renal lead level(2.58±0.21) μg·g^-1 in the lead exposure group were higher than those in the control group(0.78±0.02)%, (1.88±0.50) μg·L^-1, and (0.04±0.01) μg·g^-1 (P < 0.05). In the lead exposure group, the morphological damage of renal proximal convoluted tubules and glomeruli was obvious, and the apoptosis rate increased compared with the control group(0.013±0.003)% vs. (0.006±0.002)%; the GSH level, T-SOD activity, and Cu/Zn-SOD activity in kidney decreased (P < 0.05), while the MDA content increased (P < 0.05); the relative expression level of Bcl-2 mRNA and the ratio of Bcl-2/Bax decreased, and the relative expression level of caspase3 mRNA increased (P < 0.05); the level of cAMP and the relative expression levels of PKA and NOX4 mRNA in renal tissues increased, and there was a positive correlation between the relative expression level of NOX4 mRNA and the level of cAMP (r=0.486, P < 0.05).

Conclusion Lead can change the activity of NOX4 and cause kidney damage, which is related to cAMP/PKA signaling pathway.