Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension.
Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus, Pds (Slc26a4) is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion exchange-mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether Pds mRNA and protein expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice, Pds mRNA increased 60%, whereas pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B intercalated cells and increased 6-fold in type B cells. Because pendrin transports HCO3- and Cl-, we tested whether DOCP treatment unmasks abnormalities in acid-base or NaCl balance in Pds (-/-) mice. In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in Pds (+/+) and Pds (-/-) mice. After DOCP treatment, weight gain and hypertension were observed in Pds (+/+) but not in Pds (-/-) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in Pds (-/-) than Pds (+/+) mice. We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis.
Verlander
Jill W
JW
Department of Medicine, University of Florida College of Medicine, Gainesville, USA.
Hassell
Kathryn A
KA
Royaux
Ines E
IE
Glapion
Dawn M
DM
Wang
Mou-Er
ME
Everett
Lorraine A
LA
Green
Eric D
ED
Wall
Susan M
SM
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D002712:Chlorides / Q000097:blood / Q000652:urine; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D008901:Mineralocorticoids; D011188:Potassium / Q000097:blood / Q000652:urine; D012964:Sodium / Q000097:blood / Q000652:urine; D000076988:Sulfate Transporters
D002352:Carrier Proteins; D002712:Chlorides; D026901:Membrane Transport Proteins; D008901:Mineralocorticoids; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D003900:Desoxycorticosterone; D012964:Sodium; D011188:Potassium