The molecular mechanisms of
melamine-induced renal toxicity have not been fully understood. The purpose of the study aimed to investigate whether
melamine and
cyanuric acid induced
NOD-like receptor family pyrin domain-containing 3 (NLRP3)
inflammasome activation in the kidney, which may contribute to abnormal water and
sodium handling in a rat model. Wistar rats received
melamine (Mel; 200 mg·kg body wt-1·day-1),
cyanuric acid (CA; 200 mg·kg body wt-1·day-1), or Mel plus CA (Mel + CA; 100 mg·kg body wt-1·day-1, each) for 2 wk. Mel + CA caused damaged tubular epithelial structure and organelles, dilated tubular lumen, and inflammatory responses. Crystals were observed in urine and serum specimen, also in the lumen of dilated distal renal tubules. The combined ingestion of Mel and CA in rats caused a markedly impaired urinary concentration, which was associated with reduced
protein expression of
aquaporin (AQP)1, 2, and 3 in inner medulla and α-Na-K-
ATPase and Na-K-2Cl transporters in cortex and outer medulla. Mel + CA treatment was associated with increased
protein expression of CD3 and
mRNA levels of CD68 and F4/80 as well as phosphorylation of NF-κB in the kidney. Mel + CA treatment increased
protein and
mRNA expression of NLRP3
inflammasome components apoptosis-associated speck-like
protein containing a caspase recruitment domain, caspase-1, and IL-1β in the inner medulla of rats. NF-κB inhibitor
Bay 11-7082 reduced IL-1β expression induced by Mel + CA and prevented downregulation of AQP2 in inner medullary collecting duct cell
suspensions. In conclusion, Mel + CA treatment caused urinary-concentrating defects and reduced expression of renal AQPs and key
sodium transporters, which is likely due to the inflammatory responses and activation of NLRP3
inflammasome induced by crystals formed in the kidney.