Hypertension Precedes Metabolic Syndrome in the ALMS1 (Alstrom Syndrome 1) Knockout Rat

다국어 초록 (Multilingual Abstract)

We previously found that Alstrom syndrome 1 protein (ALMS1) is expressed in the kidney where it regulates thick ascending limb (TAL) NaCl reabsorption by controlling NKCC2 endocytosis. In humans, inactivating mutations in the ALMS1 gene causes obesity, insulin resistance and hypertension (metabolic syndrome). We found that deletion of ALMS1 in (Dahl salt‐sensitive) rats induced hypertension (measured by radio‐telemetry and tail‐cuff plethysmography). Moreover, the ALMS1 Knockout (ALMS1 KO) rats are hyperphagic and develop progressive obesity over time. Obesity is a risk factor for hypertension and insulin resistance. However, it is unclear whether the increase in blood pressure (BP) occurs prior to or after the development of metabolic alterations (obesity and insulin resistance) in the ALMS1 KO rats. We hypothesize that hypertension in the ALMS1 KO rats is primarily caused by a renal defect and not secondary to the metabolic syndrome. In order to study this we obtained young (shortly after weaning) ALMS1 KO and wild‐type (WT) rats (age range: 5–7 weeks old) and measured body weight, baseline blood glucose, glucose tolerance (IP injection of 2 kg/g of BW glucose) and systolic blood pressure (SBP) by tail‐cuff over time. ALMS1 KO (n=6) and WT (n=6) rats were given 30 g per day of regular chow (0.4% Na) with free access to water. At 5–7 weeks of age ALMS1 KO rats had similar body weights (ALMS1 KO: 209±13 g vs. WT: 182±15 g, N.S.). Baseline glucose was similar (ALMS1 KO: 88±3 vs. WT: 75±7 mg/dL, N.S.) and glucose tolerance test produced similar peaks and area under the curve. Importantly, the SBP was higher in ALMS1 KO rats (ALMS1 KO: 156±5 vs. WT: 143+3 mmHg, p<0.05). Four weeks later (9–11 weeks old), body weight began to diverge between strains (ALMS1 KO: 326±10 g vs. WT: 282±17 g, p<0.05). Baseline glucose was higher in ALMS1 KO (ALMS1 KO: 84±2 vs. WT: 71±3 mg/dL, p<0.05) and glucose tolerance test produced a higher peak in ALMS1 KO (ALMS1 KO: 376±27 vs. WT: 305±17 mg/dL, p<0.05), as well as a larger area under the curve (ALMS1 KO: 11915±1349 vs. WT: 9176±916 mg*min/dL). Lastly, the SBP continued to be elevated in the ALMS1 KO rats (ALMS1 KO: 160±3 vs. WT: 144±3 mmHg, p<0.05). Therefore, our data show that the genetic deletion of ALMS1 causes hypertension in rats and that the increase in blood pressure precedes the development of obesity and insulin resistance in this model. This is a new rat model of metabolic syndrome with established hypertension that does not require a high salt diet. Ongoing experiments will test whether caloric restriction prevents or decrease the hypertension and metabolic syndrome in this rat strain.
Support or Funding Information
NIH F31 Diversity Grant: 5F31HL123285 (King‐Medina)and NIH‐NIDDK Grant: 5R01DK107263 (Ortiz)
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.