The Effect of Combined Inhibition of mTORC1+2 on Sodium Handling in Dahl Salt‐Sensitive Rats
Authors: Evans Louise Christine , Wollner Clayton , Kurth Theresa , Cowley Allen 
Published: June 2021

Introduction

The involvement of mTOR signaling in the regulation of cell‐cycle events and human cancers has been extensively studied. In contrast, relatively little is known about the role of the kinases in cardiovascular disease, and in particular, the renal control of blood pressure.

Recent studies from our lab have demonstrated the anti‐hypertensive effect of PP242 (a combined mTORC1+mTORC2 inhibitor) in Dahl salt‐sensitive (SS) rats. We found that daily i.p. administration of PP242 to SS rats prevented the hypertensive response to 21‐days of a high‐salt diet (4.0% NaCl) and greatly attenuated renal injury. Our current studies are directed towards understanding the potential mechanisms underlying the antihypertensive effects of PP242.

Methods

To determine the effects of chronic PP242 on sodium balance, studies were performed in conscious SS rats fed either a 0.4% NaCl control salt diet or a 4.0% NaCl high salt diet and treated i.p. daily with either vehicle or PP242. Rats were surgically prepared with a femoral arterial catheter for the assessment of mean arterial pressure (MAP) and given 7 days to recover during which they were fed a 0.4% NaCl diet. Daily urine collections and measurement of food intake were then began for the balance study, which included 3‐days with rats fed the 0.4% NaCl control diet followed by 4‐days of the same diet with daily administration of PP242 or vehicle. Rats were then switched to the high 4.0% NaCl diet for 5 days while continuing to receive daily PP242 or vehicle. MAP was recorded each day (9am–12pm) throughout the study and electrolyte balance was calculated as intake – excretion.

Results

When maintained on a control‐salt diet PP242 resulted in a moderate but significant reduction of MAP, from an average of 119±3 mmHg during the control period to 106±4 mmHg after 4‐days of PP242 (n=5, p=0.014). This decrease was not observed in vehicle treated rats (average control: 121 ± 4 mmHg vs. control salt day‐4: 128 ± 4 mmHg, n=4, p=0.482). Average sodium balance tended to be negative in the PP242 treated rats during this period but did not reach significance. I.P. administration of PP242 blunted the hypertensive response to the 4.0% NaCl high‐salt diet observed in the vehicle treated rats with MAP being significantly lower than the vehicle treated group on days 1, 2, 3 and 4 of high‐salt (p<0.05, n=4 and 5).

Administration of PP242 caused a significant reduction in food intake with the cumulative food intake being 30% lower in the PP242 treated group than the vehicle treated group during the treatment period. This resulted in a significantly lower sodium intake in the PP242 treated group relative to the vehicle group on days 1,2 and 4 of high‐salt (p<0.05, n=7+6). Consequently, daily sodium excretion was significantly lower in the PP242 treated rats than the vehicle treated rats on days 1,2,3 and 4 of high‐salt days (p<0.05, n=7+6). Despite this, sodium balance was significantly lower in the PP242 treated rats than the vehicle treated rats on high‐salt day 2 (vehicle: 1387 ± 360 vs. PP242: 40 ± 280) representing a natriuretic response to PP242 and an overall negative sodium balance.

Conclusion

Together these data indicate that the antihypertensive effects of PP242 may in part be due to renal natriuretic effects induced by the combined inhibition of mTORC1 and 2.

Support or Funding Information

AHA SDG 17SDG33660574 to LE, NIH P01 HL116264 to AC

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.