Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity

Abstract

A high-fructose (HF) diet is shown to induce salt-sensitive hypertension but the underlying mechanism largely remains unknown. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. In Sprague-Dawley rats, HF intake increased renal expression of full-length PRR (fPRR), which were attenuated by allopurinol. HF intake also upregulated renal mRNA and protein expression of sodium/hydrogen exchanger 3 (NHE3) and Na/K/2Cl cotransporter (NKCC2) as well as in vivo NKCC2 activity, all of which were nearly completely blocked by a PRR decoy inhibitor PRO20 or allopurinol treatment. Parallel changes were observed for indices of intrarenal renin-angiotensin-system (RAS) including renal and urinary renin and angiotensin II levels. Radiotelemetry demonstrated that HF or a high-salt diet alone did not affect mean arterial pressure (MAP), but the combination of the two maneuvers induced a ~10 mm Hg increase of MAP, which was blunted by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid (UA) increased protein expression of soluble PRR (sPRR) in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via UA stimulates renal expression of PRR/sPRR that stimulate NHE3 and NKCC2 expression and intrarenal RAS to induce salt-sensitive hypertension.

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

“…Mice heterozygous for PRR deletion in nephron progenitor cells (homozygous deletion leads to early neonatal death) have fewer glomeruli and altered glomerular basement membrane ultrastructure and experience develop hypertension at 2 months of age, 42 suggesting that early loss of PRR may be involved in developmental programming of hypertension. Recently, Xu et al 43 found increased renal PRR expression, activation of the intrarenal RAS, and salt-sensitive hypertension in rats fed a high-fructose diet; treatment with PRO20 reduced highfructose-induced sodium retention, BP, and intrarenal RAS activation. Polycystic kidney disease is associated with early onset of hypertension, and an animal model of polycystic kidney disease had increased renin expression in cysts and mislocalization of the PRR from the luminal membrane of intercalated cells to the basolateral membrane of principal cells.…”

Multilayered Interplay Between Fructose and Salt in Development of Hypertension

“…60 Fructose-induced local uric acid production is a potent stimulator of renal full length and soluble PRR ((pro)renin receptor) expression and local intrarenal renin-angiotensin system activation. 25,61 Both PRR blockade and prevention of uric acid formation by the xanthine-oxidase inhibitor, allopurinol, independently prevented the hypertensive cascade to the dietary combination of fructose and salt in rats. 25 Around 65% of filtered sodium is reabsorbed in proximal tubules via the NHE3 in an angiotensin II-sensitive manner.…”

“…25,61 Both PRR blockade and prevention of uric acid formation by the xanthine-oxidase inhibitor, allopurinol, independently prevented the hypertensive cascade to the dietary combination of fructose and salt in rats. 25 Around 65% of filtered sodium is reabsorbed in proximal tubules via the NHE3 in an angiotensin II-sensitive manner. [62][63][64][65] A high-fructose diet enhances NHE3 expression and activity, increases intracellular angiotensin II levels and sensitizes the cell to angiotensin II, thus increasing Na reabsorption and water retention by proximal tubules.…”

“…[18][19][20] Furthermore, we have not observed metabolic effects from artificial sugars, 21 although one group did report that saccharin might induce insulin resistance in mice. 22 Rather, animals studies suggest fructose may induce hypertension by a variety of mechanisms, including fructose-induced salt and water retention, [23][24][25] insulin resistance, 26 increased serum uric acid levels, 27 decreased renal nitric oxide availability, 28 and, recently, in utero programming of hypertension. 29 Here we review more recent studies, particularly focusing on the complex synergism between sugar and salt in the development of hypertension ( Figure 1).…”

Integrative Physiological Aspects of Brain RAS in Hypertension

“…Central ACE2 has been shown to modulate NO synthesis, spontaneous baroreflex sensitivity (sBRS), and parasympathetic tone, suggesting a role for the development of neurogenic hypertension [14,18,19,102,103]. ACE2 expression and activity have been identified in multiple cardiovascular areas in the brain [47] and are thought to be the predominant enzyme involved in hydrolyzing central Ang II to Ang 1-7 in humans [104]. Central ACE2 downregulation has been observed in a number of animal hypertensive models [102,105,106].…”