High plasma soluble prorenin receptor (sPRR) levels correlate with systolic blood pressure in aged male but not in female mice

Abstract

Elderly subjects are predisposed to intrarenal renin‐angiotensin system (RAS) activation, which increases the risk for hypertension, kidney injury, and chronic kidney disease (CKD). The prorenin receptor (PRR), a component of the RAS that enhances the activity of renin and fully activates prorenin, is upregulated in the kidney in hypertensive rodent models. PRR possesses two molecular forms, a cell membrane bound and a soluble form (sPRR). Levels of sPRR in plasma are elevated in patients with cardiovascular diseases, including hypertension, preeclampsia, diabetes, and CKD. In the present study we tested the hypothesis that age increases plasma sPRR, blood pressure, and renal function in mice. We used male and female C57Bl/J6 mice distributed in 4 groups according with age (months, m) and sex (♂/♀) as follows: 1) 4–6 m, N=8/5; 2) 8–10 m, N=8/7; 3) 15–19 m, N=12/7; and 4) +20 m, N=9/7. Systolic blood pressures (SBP, mm Hg) measured by the tail cuff method were increased in male mice in 15–19 m (118±1.9) and +20 m (129±2.9) groups, compared to 4–6 m (103.0±1.8) and 8–10 m (105.0±1.6); p<.0001). No significant changes in SBP were observed in females. SBP positively correlated with age in male mice only (r=0.669; p=0.001). Plasma sPRR levels measured by ELISA (IBL America, Inc) did not differ between male and female young mice (10 m or younger). However, plasma sPRR levels were significantly higher in male mice of 15–19 m (3.8±0.2 ng/ml) and even greater in older mice (+20 m: 4.9±0.4 ng/ml), compared to 4–6 m (1.8±0.2 ng/ml) and 8–10 m (1.8±0.1 ng/ml) (p<.001). In contrast, only female mice older than 20 m of age showed significant increased plasma sPRR (4.3±0.1 ng/ml) compared to younger mice (p=0.03). Interestingly, plasma sPRR was positively correlated with SBP (r=0.602, p=0.02) in males but not in females. No differences were found in plasma and urine creatinine, osmolality, and BUN, or in urinary sodium concentration and proteinuria among groups. We conclude that: 1) Age positively correlates with SBP in male mice but not in females; 2) Plasma sPRR levels increase with age in male and female mice; and 3) Plasma sPRR levels are associated with SBP in aged males but not in female mice. The data suggests that age‐associated increases in plasma levels of sPRR and SBP are more sensitive to advanced age in male than in female C57Bl/6J mice. Further studies are needed to define whether hormone effects on plasma sPRR and SBP are independent or not of age.Support or Funding InformationSupport from NIH‐NIDDK (R01DK104375) to MCP; NIH‐NIA (R01AG047296) to RMThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Obesity Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice

“…The adipose tissue and liver have been previously demonstrated to be important sources of circulating sPRR (29, 30). In clinical studies, plasma sPRR is elevated in obese subjects (25, 31), and studies in mice show elevated plasma sPRR in obese male but not female mice (23). Likewise, in our study, obese Adi-HsPRR male but not female mice displayed increased plasma sPRR signifying that sPRR in adipose tissue may affect circulating sPRR levels in males but not females.…”

“…Still studies in male mice show that plasma sPRR could be implicated in glucose and insulin homeostasis. In obese male mice with hyperglycemia and hyperinsulinemia, plasma sPRR was elevated (23). However, exogenous addition of sPRR has been demonstrated to promote adipose tissue beigeing in male mice (33) and improve glucose and insulin balance in morbidly obese male mice (19).…”

“…For instance, in a mouse model of whole-body loss of sPRR, body weight was reduced in male mice (21) and infusion of sPRR increased body weight in male mice fed a HFD (22). Furthermore, HFD-induced obesity in male mice, elevated plasma sPRR leading to hyperglycemia, hyperinsulinemia and glucose intolerance, characteristic of type 2 diabetes (T2D) (23). Yet, in another model of HFD-induced obesity, sPRR infusion in male mice reduced body weight and improved glucose and insulin sensitivity by increasing adipose glucose transporter type 4 (Glut 4) and the phosphorylation of proteins kinase B (Akt) (19).…”

Renal-Derived Human sPRR Does Not Increase Blood Pressure in High Fat Diet Mice

“…Additionally, obese male CD-HsPRR mice have an increase in α-and ENaC protein expression along with renin and AT1R mRNA expression. The role of sPRR in obesity-related hypertension in male mice has been well demonstrated (52–54). Male mice fed a high fat diet for 32 weeks showed elevated plasma sPRR was associated with activation of systemic RAS, vascular damage, and non-dipping hypertension (54).…”

“…The role of sPRR in obesity-related hypertension in male mice has been well demonstrated (52–54). Male mice fed a high fat diet for 32 weeks showed elevated plasma sPRR was associated with activation of systemic RAS, vascular damage, and non-dipping hypertension (54). Similarly, obese male mice fed 32 weeks of HFD and infused with sPRR had hypertension due to endothelial dysfunction mediated by the activation of AT1R (52).…”