Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

Abstract

Purpose of Review Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine. Recent Findings Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Summary Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.

Sex differences in soluble prorenin receptor in patients with type 2 diabetes

“…Urine renin activity may reflect the severity of kidney dysfunction, which emphasizes its importance as a potential marker of maladaptive intrarenal/intratubular RAS activation in patients with type 2 diabetes. The fact that prorenin has been reported as undetectable in the urine [47,48] is consistent with reabsorption of renin by the proximal tubules [49,50] and that renin in urine does not reflect prorenin conversion to renin in the intratubular compartment [50,51]. Unfortunately, most of the studies reporting renin levels in urine utilize commercially available ELISA kits, which rely on prorenin as the standard provided.…”

“…In the present study, the fact that renin activity measured by radioimmunoassay was increased in urine four- and three-fold in men and women with type 2 diabetes, respectively, suggests that active renin was probably generated further down in the distal nephron segments. Recent studies reported that megalin reabsorbs renin in the proximal tubules since megalin knockout mice exhibited excessive urinary excretion of renin [ 49 , 50 ]. Megalin is primarily expressed in the apical brush border of the proximal tubules and contributes to reabsorption of filtered molecules [ 53 ].…”

The evolving complexity of the collecting duct renin–angiotensin system in hypertension

“…The observation that AGT excretion parallels albuminuria in humans but that urinary renin levels relative to albumin excretion are much higher than urinary AGT, suggests that urinary renin levels reflect not only the release of renin by the collecting duct but also renin that is filtered and incompletely reabsorbed by the proximal tubules 138 . Under normal circumstances, the reabsorption of renin and prorenin by the proximal tubule is extensive -potentially close to 100% -suggesting that very little filtered renin and prorenin escapes into the urine 139 . Given this extensive reabsorption of renin and prorenin by the proximal tubule, the finding that prorenin is not detectable in urine 15,116 , despite the fact that renin and prorenin are filtered in larger amounts than albumin, indicates that urinary renin may not reflect the conversion of prorenin to renin in tubular fluid and rather reflects intrarenal renin production 119,139 .…”

“…Under normal circumstances, the reabsorption of renin and prorenin by the proximal tubule is extensive -potentially close to 100% -suggesting that very little filtered renin and prorenin escapes into the urine 139 . Given this extensive reabsorption of renin and prorenin by the proximal tubule, the finding that prorenin is not detectable in urine 15,116 , despite the fact that renin and prorenin are filtered in larger amounts than albumin, indicates that urinary renin may not reflect the conversion of prorenin to renin in tubular fluid and rather reflects intrarenal renin production 119,139 . One study 13 showed that renin was increased in the urine of patients with type 1 diabetes mellitus and kidney disease, as well in mice with streptozotocin-induced diabetes 13 .…”

“Nomen not est omen”: the (pro)renin receptor and receptor-mediated endocytosis in the proximal tubule—a new (pro)renin-independent role forATP6ap2

“…The (pro)renin receptor was shown to be involved in the megalin-mediated uptake of renin and other components of the RAS in cell cultures in vitro. [ 9 ]. The present study now provides a good argument that this may happen also in vivo, providing another argument for renin uptake as a source for local RAS activity in the kidney.…”