Inhibition of Mast Cell Degranulation With Cromolyn Sodium Exhibits Organ-Specific Effects in Polycystic Kidney (PCK) Rats.

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a monogenic disease characterized by development of hepatorenal cysts, pericystic fibrosis, and inflammation. Previous studies show that mast cell (MC) mediators such as histamine induce proliferation of cholangiocytes. We observed robust MC accumulation around liver cysts, but not kidney cysts, in polycystic kidney (PCK) rats (an animal model of ARPKD). Therefore, we hypothesized that MCs contribute to hepatic cyst growth in ARPKD. To test this hypothesis, we treated PCK rats with 1 of 2 different MC stabilizers, cromolyn sodium (CS) or ketotifen, or saline. The CS treatment decreased MC degranulation in the liver and reduced serum tryptase (an MC granule component). Interestingly, we observed an increase in liver to body weight ratio after CS treatment paralleled by a significant increase in individual cyst size. Hepatic fibrosis was not affected by CS treatment. The CS treatment increased hepatic cyst wall epithelial cell (CWEC) proliferation and decreased cell death. Ketotifen treatment also increased hepatic cyst size. In vitro, CS treatment did not affect proliferation of isolated hepatic CWECs from PCK rats. In contrast, CS decreased kidney to body weight ratio paralleled by a significant decrease in individual cyst size. The percentage of kidney to body weight ratio was strongly correlated with serum renin (an MC granule component). Ketotifen did not affect kidney cyst growth. Collectively, these data suggest that CS affects hepatic and renal cyst growth differently in PCK rats. Moreover, CS may be beneficial to renal cystic disease but may exacerbate hepatic cyst growth in ARPKD.

• Authors: Lu Jiang, Pingping Fang, Seth Septer, Udayan Apte, Michele T Pritchard
• Journal: International journal of toxicology (Int J Toxicol) 2018 Jul/Aug Vol. 37 Issue 4 Pg. 308-326 ISSN: 1092-874X [Electronic] United States
• PMID: 29862868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cromolyn Sodium

Topics

• Animals
• Cell Degranulation (drug effects)
• Cromolyn Sodium (pharmacology)
• Disease Models, Animal
• Kidney (drug effects, physiology)
• Liver (drug effects, physiology)
• Mast Cells (drug effects, physiology)
• Polycystic Kidney, Autosomal Recessive
• Rats, Sprague-Dawley