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Metabolic Acidosis, Ocular Pressure and Cysts in NBCe1 Knockout
Author(s) -
Hildenbrand Jordan,
Chen AnPing,
Landry Greg,
Holmes Heather,
Chang MinHwang,
Romero Michael
Publication year - 2015
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.29.1_supplement.844.23
Subject(s) - glaucoma , endocrinology , medicine , intraocular pressure , knockout mouse , metabolic acidosis , blood pressure , acidosis , chemistry , ophthalmology , receptor
Background Human mutations in the Na + bicarbonate cotransporter NBCe1 (Slc4a4) cause proximal renal tubular acidosis (pRTA), cataracts & glaucoma. We reported that whole‐gene nbce1 knockouts (KO) are acidotic (blood pH <7.1) and aged, heterozygous mice (HET) have ↑IOP (intraocular pressure) [ IVOS 2013]. One patient (Q29X; only affects NBCe1A, i.e., kidney & eye), has pRTA & glaucoma. We characterized the phenotypes of an NBCe1A isoform‐knockout mouse (KO A ) and compare to HET & KO phenotypes, & to nbce1A mice (HET A , WT A ). Methods: We mated HET mice to generate KO's. Using TALEN‐technology, we generated an isoform, KO A mouse [ IVOS 2014]. IOPs were measured with a rebound Tonometer. Blood chemistries were measured using a pHOx Ultra analyzer. Kidneys and eyes were fixed, embedded and sectioned for histology. Results: Both KO & KO A are runted. KO A mice live longer than KO mice (>400 d vs 18 d). Both KO A and KO mice are acidotic (7.10±0.07; 7.08±0.04) with low blood [HCO 3 ‐ ] (mM:7.2±1.5; 4.6±1.0). KO A and KO mice have elevated renin, angiotensin II, and aldosterone levels, i.e. RAAS activation. As HETs age (>1y), their IOP's ↑(19.8 mmHg) while WT IOPs (15.2 mmHg) do not. KO A mice show ↑IOP at ~1y (17.6 mmHg) compared to HET A & WT A (15.2, 12.7 mmHg). Renal histology of KO & KO A show cortical cysts. Conclusions KO A mice survive longer (>1y), are acidotic, have ↑IOP and cysts. The onset age of ↑IOP is later and less extreme than IOP & pH of whole‐gene nbce1 KO. Thus, NBCe1A is the major renal HCO 3 ‐ absorption path, is RAAS controlled, controls ocular fluid transport (ΔIOP) and causes cysts. These mice should facilitate both aging and systemic disease studies. Support: DK101405; Kogod Aging Center