title: Pappa2 is linked to salt-sensitive hypertension in Dahl S rats.
abstract: A 1.37 Mbp region of chromosome 13 previously identified by exclusion mapping was consistently associated with a reduction of salt-induced hypertension in the Dahl salt-sensitive (SS) rat. This region contained five genes that were introgressed from the salt-insensitive Brown Norway (BN) rat. The goal of the present study was to further narrow that region to identify the gene(s) most likely to protect from salt-induced hypertension. The studies yielded a subcongenic SS rat strain containing a 0.71 Mbp insert from BN (26-P strain) in which salt-induced hypertension was reduced by 24 mmHg. The region contained two protein-coding genes (Astn1 and Pappa2) and a microRNA (miR-488). Pappa2 mRNA in the renal cortex of the protected 26-P was 6- to 10-fold greater than in SS fed a 0.4% NaCl diet but was reduced to levels observed in SS when fed 8.0% NaCl diet for 7 days. Compared with brain nuclei (NTS, RVLM, CVLM) and the adrenal gland, Pappa2 in the renal cortex was the only gene found to be differentially expressed between SS and 26-P and that responded to changes of salt diet. Immunohistochemistry studies found Pappa2 localized in the cytosol of the epithelial cells of the cortical thick ascending limbs. In more distal segments of the renal tubules, it was observed within tubular lumens and most notably bound to the apical membranes of the intercalated cells of collecting ducts. We conclude that we have identified a variant form of Pappa2 that can protect against salt-induced hypertension in the Dahl S rat.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; cowley@mcw.edu.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cowley
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Vikash
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Howard
authors.initials: H
authors.lastname: Jacob
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Alex
authors.initials: A
authors.lastname: Dayton
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Theresa
authors.initials: T
authors.lastname: Kurth
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Mingyu
authors.initials: M
authors.lastname: Liang
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000419:Albuminuria / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001794:Blood Pressure; D001933:Brain Stem / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D016678:Genome; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020303:Rats, Inbred Dahl; D017422:Sequence Analysis, DNA; D049992:Sodium Chloride Symporters / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: D012333:RNA, Messenger; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D011266:Pregnancy-Associated Plasma Protein-A
keywords: Astn1; Dahl S rats; ENaC; Na excretion; Pappa2; congenic; genetics; intercalated cells; kidney; miR-488; renal collecting ducts; thick ascending limbs