title: On the Origin of Urinary Renin: A Translational Approach.
abstract: Urinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin's precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than albumin and angiotensinogen, and that differences in excretion rate are because of a difference in reabsorption in the proximal tubule. To address this, we determined the glomerular sieving coefficient of renin and prorenin and measured urinary renin/prorenin 1) after inducing prorenin in Cyp1a1-Ren2 rats and 2) in patients with Dent disease or Lowe syndrome, disorders characterized by defective proximal tubular reabsorption. Glomerular sieving coefficients followed molecular size (renin>prorenin>albumin). The induction of prorenin in rats resulted in a >300-fold increase in plasma prorenin and doubling of blood pressure but did not lead to the appearance of prorenin in urine. It did cause parallel rises in urinary renin and albumin, which losartan but not hydralazine prevented. Defective proximal tubular reabsorption increased urinary renin and albumin 20- to 40-fold, and allowed prorenin detection in urine, at ≈50% of its levels in plasma. Taken together, these data indicate that circulating renin and prorenin are filtered into urine in larger amounts than albumin. All 3 proteins are subsequently reabsorbed in the proximal tubule. For prorenin, such reabsorption is ≈100%. Minimal variation in tubular reabsorption (in the order of a few %) is sufficient to explain why urinary renin and albumin excretion do not correlate. Urinary renin does not reflect prorenin that is converted to renin in tubular fluid.
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Lodi C W
authors.initials: LC
authors.lastname: Roksnoer
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Bart F J
authors.initials: BF
authors.lastname: Heijnen
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Walsh
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Jeanette M G
authors.initials: JM
authors.lastname: van Gool
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Harry A J
authors.initials: HA
authors.lastname: Struijker-Boudier
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.).
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
authors.affiliation: From the Division of Pharmacology and Vascular Medicine (L.C.W.R, I.M.G., J.M.G.v.G., A.H.J.D.), Division of Nephrology and Transplantation (L.C.W.R., R.Z., E.J.H.), Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (B.F.J.H., H.A.J.S.-B.); Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles (D.N., J. P.-P.); Department of Pharmacology, Kagawa University, Kagawa, Japan (D.N.); and UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom (S.B.W.). a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D057973:Dent Disease / Q000503:physiopathology / Q000652:urine*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009800:Oculocerebrorenal Syndrome / Q000503:physiopathology / Q000652:urine*; D051381:Rats; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012494:Sampling Studies; D057170:Translational Research, Biomedical / Q000379:methods*; D016482:Urinalysis; D055815:Young Adult
chemical_list: D000418:Albumins; D000808:Angiotensinogen; D012083:Renin
keywords: Dent disease; Lowe syndrome; angiotensinogen; glomerular filtration barrier; renin