Abstract
The urinary excretion of renin–angiotensin system (RAS) proteins could reflect the activity of the intrarenal RAS. We hypothesized that the rates of excretion of RAS components into human urine are independent of circulating levels of these proteins and reflect the intrarenal RAS. There are no reports of the simultaneous measurement of prorenin, active renin, angiotensinogen (AGT), and angiotensin-converting enzyme (ACE) excretion in healthy individuals. Therefore, we measured plasma prorenin, ACE, and AGT and urinary renin (uRenin), prorenin (uProrenin), ACE (uACE), and AGT (uAGT) in men and nonpregnant women. Plasma (p) AGT was higher in women then men. Women who were taking estrogen had significantly higher pAGT. In women, pProrenin was negatively correlated with pAGT. There were no correlations between pProrenin, pAGT, and pACE and their urinary counterparts in either men or women. In men, uProrenin/creatinine ratios were lower than in women. There was no effect of estrogen use on urinary excretion of pProrenin, renin, AGT, and ACE. In men, there were significant correlations between uACE/creat and uRen/creat and uAGT/creat; uProrenin/creat and plasma cystatin C levels; and uRenin/creat and uNa/K were also positively correlated. No associations were found in women. In conclusion, urinary excretion of prorenin is sexually dimorphic and is not affected by estrogen use in women. Our data also suggest that the relationship between renal handling of sodium and urinary renin is sexually dimorphic. Since we found no associations between plasma RAS proteins and their urinary counterparts, and the ratio of uProrenin:pProrenin was strikingly different between men and women, levels of urinary RAS proteins in individuals with normal kidney function are most likely the result of tubular secretion, rather than ultrafiltration.
Highlights
There is growing interest in the urinary excretion of renin– angiotensin system (RAS) proteins because it is claimed that urinary angiotensinogen, in particular, reflects the activity of the intrarenal RAS. uAGT levels are elevated in patients with chronic kidney disease (CKD) and diabetic nephropathy (Yamamoto et al 2007; Kobori et al 2008; Urushihara et al 2010; van den Heuvel et al 2011; Kobori and Navar 2011; Nishiyama et al 2011; Roksnoer et al 2013) and are reduced when patients are treated with RAS blocking drugs (Kobori et al 2009; Urushihara et al 2010)
Women who were taking estrogen-containing medications had higher pAGT levels (Fig. 2) because AGT has an estrogen-sensitive response element situated between the TATA box and the start of the transcription site (Derkx et al 1986; Yanai et al 1996; van den Heuvel et al 2011)
The high pAGT presumably acts via a negative feedback pathway to inhibit renin and prorenin release from the kidney, as has been found in other studies where both prorenin and active renin levels are lower in women taking oral contraceptives (Derkx et al 1986; Danser et al 1998)
Summary
There is growing interest in the urinary excretion of renin– angiotensin system (RAS) proteins because it is claimed that urinary angiotensinogen (uAGT), in particular, reflects the activity of the intrarenal RAS. uAGT levels are elevated in patients with chronic kidney disease (CKD) and diabetic nephropathy (Yamamoto et al 2007; Kobori et al 2008; Urushihara et al 2010; van den Heuvel et al 2011; Kobori and Navar 2011; Nishiyama et al 2011; Roksnoer et al 2013) and are reduced when patients are treated with RAS blocking drugs (Kobori et al 2009; Urushihara et al 2010).The presence of angiotensin-converting enzyme (ACE) (Kokubu et al 1978; Ura et al 1985), renin (Lumbers and Skinner 1969a,b; Haley and Johnson 1978), and AGT (Lumbers and Skinner 1969a; Favaro et al 1972) in urine has previously been described, there are very few studies comparing their excretion rates within the same individual even though all these components are distributed along the renal tubule (Lumbers and Skinner 1969a; Darby and Sernia 1995; Metzger et al 1999; Rohrwasser et al 1999).Intrarenal generation of Ang II and subsequent binding of angiotensin II (Ang II) to the Ang II type 1 receptor a 2015 The Authors. Circulating and Intrarenal RAS in Healthy Individuals (AT1R) causes direct renal vasoconstriction, alters sensitivity of the tubuloglomerular feedback mechanism and stimulates proximal and distal tubular sodium reabsorption (Braam et al 1993; Navar 1997). This tubular Ang II/AT1R interaction has been shown to be responsible for the maintenance of hypertension in mice chronically infused with Ang II (Crowley et al 2005, 2006)
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