Abstract 103: Decreased Ability to Excrete a Na Load and Hypertension in the ALMS1 (Alstrom Syndrome 1) Knockout Rat

Abstract

Few genes involved in obesity are known to be involved in hypertension. The Alstrom Syndrome 1 protein (ALMS1) is involved in obesity in humans. We found it is expressed in the thick ascending limb (TAL) where it interacts with the Na/K/2Cl cotransporter (NKCC2). ALMS1 is also expressed in other nephron segments such as the proximal tubule and collecting ducts. We hypothesized that ALMS1 deletion leads to hypertension which is likely due to a decrease ability to excrete a salt load secondary to enhanced NaCl transport by the TAL and other nephron segments. To study the role of ALMS1 in renal function we generated ALMS1 knockout (KO) rats in a Dahl-salt sensitive genetic background via zinc-finger nuclease targeting by MCW gene targeting core. Using radio-telemetry we found the KO rats to have a higher baseline systolic blood pressure on normal Na chow compared to the Wild-type salt sensitive (WT) rats (KO:146±2 and WT:136±1 mmHg, *p=0.0012). To explore whether hypertension is related to increase renal Na reabsorption in KO rats we performed metabolic cage protocols to measure the acute excretion of a Na load (1% of body weight) in conscious rats. Our data show that it took longer for KO rats to excrete the Na load; cumulative or at individual time points (6, 9, 24 h) (cumulative Na, KO:4251±590 μmols/24h and WT:8788±994 μmols/24h, *p=0.0028). To test the role of different nephron segments in higher Na reabsorption we used a single dose of diuretics and measured urine Na and volume excretion. The NKCC2 inhibitor bumetanide (5mg/kg), induced a higher natriuretic response in KO rats (KO:485.2±37.1 μmols/8h, WT:221.8±32 μmols/8h, *p<0.05). The NCC inhibitor hydrochlorothiazide (HCTZ) 200mg/kg, caused a similar natriuretic effect in KO rats (KO:206.8±16 μmols/8h and WT:155.6±20 μmols/8h, p=0.0717). The ENaC inhibitor benzamil (10mg/kg), caused a similar natriuretic response in KO rats (KO:214.5±33 μmols/8h and WT:253.4±22 μmols/8h, p=0.3477). We conclude that ALMS1 KO have a decreased ability to excrete a salt load and this is primarily mediated by enhanced TAL-mediated Na reabsorption. Higher TAL Na absorption is likely involved in hypertension in ALMS1 KO rats. These data show that ALMS1 is important for blood pressure control and renal function.