Soluble Prorenin Receptor Increases Blood Pressure in High Fat–Fed Male Mice

Abstract

Obesity-related hypertension is a major public health concern. We recently demonstrated that plasma levels of the soluble form of the prorenin receptor (sPRR) were elevated in obesity-associated hypertension. Therefore, in the present study, we investigated the contribution of sPRR to blood pressure (BP) elevation in the context of obesity. High fat–fed C57BL/6 male mice were infused with vehicle or sPRR (30 µg/kg per day) via subcutaneously implanted osmotic minipump for 4 weeks. BP parameters were recorded using radiotelemetry devices. Male mice infused with sPRR exhibited higher systolic BP and mean arterial pressure and lower spontaneous baroreflex sensitivity than mice infused with vehicle. To define mechanisms involved in systolic BP elevation, mice were injected with an AT1R (Ang II [angiotensin II] type 1 receptor) antagonist (losartan), a muscarinic receptor antagonist (atropine), a β-adrenergic antagonist (propranolol), and a ganglionic blocker (chlorisondamine). Losartan did not blunt sPRR-induced elevation in systolic BP. Chlorisondamine treatment exacerbated the decrease in mean arterial pressure in male mice infused with sPRR. These results demonstrated that sPRR induced autonomic nervous dysfunction. Interestingly, plasma leptin levels were increased in high fat–fed C57BL/6 male mice infused with sPRR. Overall, our results indicated that sPRR increased systolic BP through an impairment of the baroreflex sensitivity and an increase in the sympathetic tone potentially mediated by leptin in high fat–fed C57BL/6 male mice.

The Pathological Role of Pro(Renin) Receptor in Renal Inflammation

“… 7 The extracellular domain can be cleaved to soluble PRR (sPRR) which is secreted into the blood and urine. 9 Binding of sPRR to prorenin leads to the generation of angiotensin II (Ang II) and mediating the effects of renin/prorenin. 10 , 11 The cytoplasmic domain complexed with V-ATPase is involved in lysosomal acidification 12 and is independent of prorenin/renin binding to PRR 13 ( Figure 1 ).…”

“… 61 In addition to the renal effects, sPRR plays a role in the impairment of the sympathetic nervous system and vascular tone. 9 , 62 In obese mice induced with sPRR, blood pressure was increased due to elevation of leptin and sympathetic activation. 63 In obesity-related hypertension sPRR has shown to impair the morphology of adipose tissue contributing to the inflammatory process.…”

“… 63 In obesity-related hypertension sPRR has shown to impair the morphology of adipose tissue contributing to the inflammatory process. 9 These effects were attenuated by knockdown of PRR suggesting that plasma leptin mediates the sPRR effect on sympathetic tone. 9 , 64 These mechanisms may be completely independent of the RAS system.…”

“… 9 These effects were attenuated by knockdown of PRR suggesting that plasma leptin mediates the sPRR effect on sympathetic tone. 9 , 64 These mechanisms may be completely independent of the RAS system. However, taken together the above studies demonstrate that renal PRR plays a prominent pathophysiological role in renal dysfunction and inflammation.…”

The interaction partners of (pro)renin receptor in the distal nephron

“…The full‐length PRR is cleaved by furin and site‐1 protease (S1P) to generate a 28‐kDa N‐terminal extracellular domain (ECD), soluble PRR (sPRR), to secrete into extracellular spaces, or retain inside the cells, and a 8.9‐kDa C‐terminal transmembrane (TM) form (M8.9) contains a single TM domain (TMD) and a short cytoplasmic domain, complexed with vacuolar H + ‐ATPase (V‐ATPase) 7,8 . sPRR is involved in a variety of physiopathological processes such as urine concentration, 9,10 diet‐induced obesity, 11 and hypertension 12 …”