High-Fructose-Induced Salt-Sensitive Hypertension: The Potential Benefit of SGLT4 or SGLT5 Modulation

Abstract

Hypertension is an important risk factor for cardiovascular diseases. High salt intake when consumed with excess fructose enhances hypertension and resultant cardiovascular disease. Usually, the small intestine absorbs dietary fructose, and the proximal tubule of kidney reabsorbs filtered fructose into the circulation with the help of different transporters including SGLT4 and SGLT5. Very recently, SGLT5 mRNA has also been found to be expressed in the heart. High-fructose diet stimulates the sympathetic nervous system and renin-angiotensin-aldosterone (RAAS) activity, of which both are responsible for endothelial dysfunction and are associated with salt-sensitive hypertension. Few studies exist regarding the effects of SGLT4 and SGLT5 on cardiovascular function and blood pressure. However, SGLT4 gene knockout does not alter fructose-associated impact on blood pressure. In contrast, blood pressure does not increase in SGLT5 knockout rats even during fructose consumption. Given that limiting fructose and salt consumption as a public health strategy has proven challenging, we hope that studies into SGLT4 and SGLT5 transporters will open new research initiatives to address salt-sensitive hypertension and cardiovascular disease. This review highlights current information about SGLT4 and SGLT5 on fructose absorption, salt-sensitive hypertension, cardiovascular disease and points the way for the development of therapeutic fructose inhibitors that limit adverse effects.

Keywords: SGLT4; SGLT5; diet; fructose; hypertension; prevention; salt.

Figure 1

Generalized secondary structure of SGLTs. The SGLT1 664-amino-acid protein contains 14 transmembrane helical domains. Note that in SGLT2, TM1 and TM6 possess breaks in their helical structure (not depicted here).

Figure 2

(A) Open chain structures for fructose and glucose. (B) Ring structures for β-D-fructofuranose and D-glucopyranose which are the favored conformations for binding and transport via GLUT transporters. (C) Ring structures for β-D-fructopyranose which is the favored conformation for transport by SGLTs tested thus far and 1,5-anhydroglucicol (1,5-AG) (see text for details).

Figure 3

Localization of different SGLTs in different organs of the body.

Figure 4

Glucose transport by SGLTs and facilitated by GLUTs in the intestine. Fructose is transported from the gut lumen into the cell primarily via GLUT5 on the apical membrane and then into the interstitium and circulation via GLUT5 on the basolateral membrane. GLUT5 can transport bidirectionally. In the intestine, SGLT4 can transport fructose but favors the transport of mannose along with Na⁺ in 1:1 ratio. Glucose enters the gut epithelium either through GLUT2 or SGLT1. The latter transports glucose in 2:1 ratio. Glucose is absorbed into the circulation after transport into the interstitium by GLUT2 on the basolateral membrane.

Figure 5

Glucose transport by active SGLTs and facilitated GLUTs in kidney. The early proximal tubule (segments S1 and S2) possesses SGLT2, SGLT4 and SGLT5 on the apical membrane. Glucose enters the cell primarily via SGLT2 in 1:1 ratio with Na⁺. The major transporter for fructose in this segment is SGLT5 although SGLT4 may also have a role. SGLT4 and SGLT5 favor mannose and fructose, respectively. Once in the cell, glucose or fructose can exit the cell via GLUT2 since GLUT5 has not yet been identified in the kidney. In the S3 segment or proximal straight tubule, SGLT1 is the primary carbohydrate transporter which reabsorbs glucose along with 2 Na⁺ ions at the apical membrane; glucose is then transported into the interstitial fluid and thereafter into bloodstream by GLUT2 on the basolateral membrane.

Figure 6

Mechanisms involved in fructose-associated salt-sensitive hypertension.