Premium
Activation of PPARγ by rosiglitazone (Ro) inhibits intestinal Cl − secretion
Author(s) -
Bajwa Poonam J.,
Lee Jimmy W.,
Straus Daniel S.,
Lytle Christian
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.934.19
Subject(s) - endocrinology , medicine , secretion , chemistry , pioglitazone , cholera toxin , enteroendocrine cell , ileum , epithelial polarity , western blot , biology , hormone , biochemistry , endocrine system , type 2 diabetes , cell , diabetes mellitus , gene
Thiazolidinedione drugs Ro and pioglitazone (Po) are PPARγ agonists in widespread clinical use as insulin‐sensitizing agents in type 2 diabetes. The effects of Ro and Po on intestinal Cl − secretion was evaluated in mice and in cultured human intestinal cells (HT29‐Cl.19A). Oral administration of Ro (20 mg/kg/day) to mice for 8 days reduced cAMP‐evoked electrogenic Cl − secretion by the terminal ileum and distal colon by 80±14%. In the proximal colon both Ca 2+ and cAMP‐evoked Cl − secretion were inhibited by 96±28% and 91±19%, respectively. In a mouse model of secretory diarrhea, Ro reduced cholera toxin‐induced fluid secretion by 52±15%. Treatment of HT29 cells with 10 μM Ro for 3 days reduced the secretory Isc evoked by either Ca 2+ (64±22%) and cAMP (52±13%). The inhibitory effect of Ro became apparent only after 3 days. Similar effects were observed with Po. Experiments with 8cpt‐cAMP indicated that inhibition occurs distal to cAMP generation. Membrane permeabilization experiments revealed that Ro inhibits both cAMP‐evoked basolateral K + conductance and apical CFTR Cl − conductance. Western blot analysis of HT29 cells indicated that chronic Ro treatment reduced CFTR channel expression by 60±20%. We conclude that Ro suppresses intestinal Cl secretion through a PPARγ‐dependent genomic mechanism that downregulates expression of apical CFTR Cl − channels and reduces expression or activity of basolateral K + channels.