Metabolic Acidosis, Ocular Pressure and Cysts in NBCe1 Knockout

Abstract

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 (KOA) and compare to HET & KO phenotypes, & to nbce1A mice (HETA, WTA). Methods: We mated HET mice to generate KO's. Using TALEN-technology, we generated an isoform, KOA 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 & KOA are runted. KOA mice live longer than KO mice (>400 d vs 18 d). Both KOA and KO mice are acidotic (7.10±0.07; 7.08±0.04) with low blood [HCO3-] (mM:7.2±1.5; 4.6±1.0). KOA 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. KOA mice show ­↑IOP at ~1y (17.6 mmHg) compared to HETA & WTA (15.2, 12.7 mmHg). Renal histology of KO & KOA show cortical cysts. Conclusions KOA 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 HCO3- 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