Exaggerated Salt‐Sensitive Hypertension in the ALMS1 (Alstrom syndrome 1) Knockout Rat

We recently found that a protein named ALMS1 (Alstrom syndrome 1) is expressed in the kidney thick ascending limb (TAL) where it mediates endocytosis of the renal Na/K/2Cl cotransporter termed NKCC2. To study the role of ALMS1 in renal physiology we generated ALMS1 knockout (KO) rats in a Dahl salt‐sensitive genetic background via zinc‐finger nuclease targeting. We previously found that the amount of NKCC2 in the apical surface is higher in the TALs from ALMS1 KO rats compared to WT‐ Salt‐Sensitive (SS) rats. In order to determine the role of NKCC2 on blood pressure (BP) we utilized both noninvasive tail cuff measurements and invasive radio‐telemetry to study the effects of dietary sodium (.22% Na chow and 4% Na chow) on the systolic blood pressure (SBP) of the ALMS1 KO rats and WT‐SS rats. We hypothesized that deletion of the ALMS1 gene will increase SBP and enhance salt‐sensitivity of BP, in part due to higher NKCC2‐mediated Na reabsorption. First, we used tail cuff measurements to obtain the SBP in both groups of rats. We found that with normal Na intake (0.22% Na chow), the ALMS1 KO rats had a higher SBP than the WT‐SS rats (KO: 136±3 and WT‐SS: 125±3 mmHg, p=0.0461). To further explore the salt‐sensitive response of these rats we utilized radio‐telemetry monitoring for 4 weeks. We found the ALMS1 KO rats to have a higher baseline SBP on .22% Na chow compared to the WT‐SS rats (KO: 145±2 and WT‐SS: 134±1 mmHg, p=0.0009 ). After 2 weeks of high Na intake (4% Na chow) the SBP in ALMS1 KO rats increased to 181±1 mmHg, a 35±3 mmHg increase, whereas the SBP increased to 159±2 mmHg in WT‐SS rats, a 25±1 mmHg increase (p<0.01 vs ALMS1 KO ) . Thus, the SBP was higher in ALMS1 KO rats fed a high salt diet (p=0.0001 ). We then explored the involvement of NKCC2 in the hypertension observed in ALMS1 KO rats. A daily dose of the loop diuretic bumetanide (3mg/kg), an NKCC2 inhibitor, decreased the SBP in both groups (KO: −23±4 and WT: −30±6 mmHg, p=0.40). After 7 days of treatment with bumetanide, the SBP was normalized only in the WT‐SS rats while the SBP remained elevated in the ALMS1 KO rats (KO: 131±3 and WT: 115±4 mmHg, p<0.025). Therefore, we conclude that the ALMS1 KO rats have a higher salt‐sensitivity of BP than the WT‐ (Dahl) SS rats and this in part is mediated by enhanced renal sodium reabsorption in the TAL. Furthermore, our data suggest that additional mechanisms are likely involved in the hypertension observed in ALMS1 KO rats fed a high salt diet. Support or Funding Information NIH F31 Diversity Grant Number: 5F31HL123285‐02