Activation of PPARgamma by rosiglitazone attenuates intestinal Cl- secretion.
The thiazolidinedione (TZD) drugs rosiglitazone (Ro) and pioglitazone (Po) are PPARgamma agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes. On the basis of recent evidence implicating PPARgamma as a positive modulator of intestinal epithelial differentiation, we hypothesized that TZD drugs might attenuate intestinal secretory function. To evaluate this possibility, we examined the effects of Ro and Po on electrogenic Cl- secretion [short-circuit current (I(sc))] in mouse intestinal segments and in cultured human intestinal epithelial cells (HT29-Cl.19A). As hypothesized, oral administration of Ro (20 mg.kg(-1).day(-1)) to mice for 8 days markedly reduced intestinal I(sc) responses to cAMP (forskolin)- and Ca2+ (carbachol)-dependent stimuli. In these Ro-treated mice, cholera toxin-induced intestinal fluid accumulation was reduced 65%. With continued Ro treatment, the I(sc) response to carbachol recovered significantly, whereas that to forskolin remained attenuated. Treatment of HT29 cells for 5 days with 10 muM Ro or Po in vitro brought about a similar hyposecretory state. In HT29 cells, the loss of cAMP-dependent Cl- secretion was attributable to a reduced expression of CFTR Cl- channel, KCNQ1 K+ channel, and Na-K-2Cl cotransporter-1 proteins. The transient loss of Ca2+-dependent Cl- secretion involved an impairment of basolateral Ca2+-stimulated K+ channel activity without a detectable loss of K(Ca)3.1 channel protein. Our results establish TZD drugs as important modulators of intestinal Cl- secretory function.
Bajwa
Poonam J
PJ
Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA.
Lee
Jimmy W
JW
Straus
Daniel S
DS
Lytle
Christian
C
D000284:Administration, Oral; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002772:Cholera Toxin; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D017097:Electric Impedance; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007419:Intestinal Secretions / Q000187:drug effects* / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
C505032:CFTR protein, human; D002712:Chlorides; D005765:Gastrointestinal Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D047495:PPAR gamma; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D002217:Carbachol; D002772:Cholera Toxin; D000242:Cyclic AMP; D002118:Calcium; D000077205:Pioglitazone