Deletion of ALMS1 (Alstrom Syndrome 1) enhances salt‐sensitive hypertension, and induces insulin resistance and obesity in rats.
Authors: Jaykumar Ankita Bachhawat , Caceres Paulo , Henson Emily L , Beierwaltes William H , Ortiz Pablo A 
Published: November 2023

The Na/K/2Cl cotransporter NKCC2 mediates NaCl absorption by the Thick Ascending Limb (TAL). Increased NKCC2 activity and apical trafficking are associated with salt sensitive hypertension in rodents and humans. A 150 amino acid region in the carboxyl terminus of NKCC2 (C‐NKCC2) was shown to be important for apical targeting of NKCC2. We hypothesized that proteins which bind to C‐NKCC2 play a role in regulating NKCC2 trafficking and activity. Using a targeted proteomics approach to screen TAL proteins that bind C‐NKCC2, we identified Alstrom syndrome 1 (ALMS1) as an interacting partner. The ALMS1 gene has been linked to hypertension and renal function in Genome Wide Association Studies. However its function in the kidney is not known. To study the role of ALMS1 we obtained ALMS1 KO rats in collaboration with the Genome Editing Rat Resource Consortium at MCW. We found that in TALs from ALMS1 KO rats, surface NKCC2 was higher due to lower rates of NKCC2 endocytosis. Thus, we hypothesized that deletion of ALMS1 would increase NKCC2‐mediated NaCl reabsorption, and induce salt sensitive hypertension. To study NKCC2‐mediated Na transport in vivo, we measured bumetanide‐induced natriuresis and diuresis. ALMS1 KO rats exhibited higher bumetanide‐induced natriuresis (ALMS: 1292 ± 65 vs WT: 564 ± 31 μmoles/8 hr, p<0.01, n=5) and diuresis (ALMS1: 3.1 ± 0.32 vs WT: 1.6 ± 0.13 ml/8 hr, p<0.05, n=5), indicative of higher TAL NaCl reabsorption. On a normal salt diet (0.22% Na in chow) and tap water, ALMS1 KO had a higher systolic blood pressure and were hypertensive (ALMS1: 147 ± 4 vs WT: 127 ± 5 mmHg, p< 0.02, n=6). Upon addition of 0.5% NaCl in drinking water for 6 days, the systolic blood pressure in ALMS1 KO rats increased in ALMS1 KO rats but not in WT rats (ΔSBP ALMS1: 12.8 ± 5 vs ΔSBP WT: 4.3 ± 7.2 mmHg, p<0.05, n=6). The hypertension and salt sensitivity appears to be independent of the renin angiotensin system because plasma renin activity was lower in ALMS1 KO rats compared to WT rats (ALMS1: 1.3 ± 0.3 vs WT: 2 ± 0.3 ng/ml/hr, p<0.05, n=6). However, we also found that at 3 months of age ALMS1 KO rats developed obesity (Body weight ALMS1: 437.2 ± 8 vs WT: 359.5 ± 5 g, p<0.01, n=5) and insulin resistance evidenced by elevated plasma insulin levels (ALMS1: 13 ± 5 vs WT: 1.8 ± 1.2 ng/ml, p<0.05, n=6) and glucose levels after fasting (ALMS1: 108 ± 20 vs WT: 61 ± 5 mg/dl, p<0.05, n=6). Combined, these data indicate that ALMS1 KO rats are hypertensive and more salt sensitive than WT controls. The mechanism causing salt‐sensitive hypertension in ALMS1 KO rats may in part be due to higher TAL NaCl reabsorption and higher NKCC2 activity. However, it is possible that insulin resistance and obesity that develops in these ALMS1 KO rats may play a role in the salt sensitivity. Thus, ALMS1 is not only important for renal function but may also be involved in the regulation of glucose homeostasis and metabolism in rats.

Support or Funding Information

1) NIH‐ NIDDK to Pablo A.Ortiz. 2) AHA‐ Grant‐in‐Aid to Pablo A.Ortiz. 3) AHA‐ Pre‐doctoral fellowship to Ankita Jaykumar.