Effects of Sleeve Gastrectomy on Blood Pressure Reduction in Diet-Induced Obese Hypertensive Rats: A Potential Role of Prouroguanylin

<b>Background/Objectives:</b> Sleeve gastrectomy (SG) is the most commonly performed bariatric surgery worldwide. It results in significant weight loss and improves metabolic disorders such as hypertension. Weight loss is thought to be the main factor contributing to blood pressure (BP) reduction after SG. Small-intestinal hormones may also mediate the antihypertensive effects of SG. We aimed to investigate the mechanisms underlying the antihypertensive effects of SG through small-intestinal hormones independently of weight loss. <b>Methods:</b> This study involved male Sprague-Dawley rats that underwent a sham operation or SG, followed by a dietary intervention involving a standard diet, a high-fat and high-salt diet, or pair-feeding with SG. <b>Results:</b> Three weeks postoperatively, SG significantly reduced systolic blood pressure (SBP) and increased urinary sodium excretion. RNA sequencing of the small intestine revealed upregulation of the gene encoding prouroguanylin (proUGN). proUGN is a small-intestinal hormone that inhibits renal sodium reabsorption by converting sodium/hydrogen ion exchanger type 3 (NHE3) in the proximal tubules into the inactive phosphorylated form at Ser552 (pS552-NHE3). Furthermore, SG significantly increased proUGN levels in the ileum and plasma, as well as the levels of pS552-NHE3 in the renal cortex. The administration of exogenous uroguanylin, which is converted from proUGN, resulted in increased renal pS552-NHE3, increased urinary sodium excretion, and decreased SBP without body weight reduction. These effects were similar to those observed with SG. <b>Conclusions:</b> SG increases proUGN secretion from the small intestine, leading to increased blood concentration. This inhibits NHE3 activity in the proximal tubules, promotes natriuresis and reduces BP.