title: Aminopeptidase N reduces basolateral Na+ -K+ -ATPase in proximal tubule cells.
abstract: Aminopeptidase N/CD13 (Anpep) is a membrane-bound protein that catalyzes the formation of natriuretic hexapeptide angiotensin IV (ANG IV) from ANG III. We previously reported that Anpep is more highly expressed in the kidneys of Dahl salt-resistant (SR/Jr) than salt-sensitive (SS/Jr) rats, Anpep maps to a quantitative trait locus for hypertension, and that the Dahl SR/Jr rat contains a functional polymorphism of the gene. This suggests that renal Anpep may be linked to salt sensitivity; however, its effect on renal Na handling has not been determined. Here, we examined regulation of basolateral Na(+)-K(+)-ATPase, a preeminent basolateral Na(+) transporter in proximal tubule cells, by Anpep in LLC-PK1 cells. Treatment of the cells with Anpep siRNA increased total cellular Na(+)-K(+)-ATPase activity and basolateral Na(+)-K(+)-ATPase abundance by approximately twofold. Conversely, Anpep overexpression reduced Na(+)-K(+)-ATPase activity and basolateral abundance by approximately 50%. Similar effects were observed after treatment with ANG IV (10 nM, x30 min and 12 h). ANG IV receptor (AGTRIV) knockdown via specific siRNA relieved the decreases in basolateral Na(+)-K(+)-ATPase levels and activity induced by Anpep overexpression. In sum, these results demonstrate that Anpep reduces basolateral Na(+)-K(+)-ATPase levels via ANG IV/AGTRIV signaling. This novel pathway may be important in renal adaptation to high salt.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Kotlo
authors.forename: Sagar
authors.initials: S
authors.lastname: Shukla
authors.forename: Urmila
authors.initials: U
authors.lastname: Tawar
authors.forename: Randal A
authors.initials: RA
authors.lastname: Skidgel
authors.forename: Robert S
authors.initials: RS
authors.lastname: Danziger
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011945:Receptors, Angiotensin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013552:Swine
chemical_list: C090830:AT4 receptor; D034741:RNA, Small Interfering; D011945:Receptors, Angiotensin; D018826:CD13 Antigens; D000254:Sodium-Potassium-Exchanging ATPase