title: The collecting duct is the major source of prorenin in diabetes.
abstract: In addition to the juxtaglomerular apparatus, renin is also synthesized in renal tubular epithelium, including the collecting duct (CD). Angiotensin (Ang) II differentially regulates the synthesis of juxtaglomerular (inhibition) and CD (stimulation) renin. Because diabetes mellitus, a disease with high intrarenal renin-Ang system and Ang II activity, is characterized by high prorenin levels, we hypothesized that the CD is the major source of prorenin in diabetes. Renin granular content was visualized using in vivo multiphoton microscopy of the kidney in diabetic Munich-Wistar rats. Diabetes caused a 3.5-fold increase in CD renin, in contrast to less pronounced juxtaglomerular changes. Ang II type 1 receptor blockade with Olmesartan reduced CD renin to control levels but significantly increased juxtaglomerular renin. Using a fluorogenic renin assay, the prorenin component of CD renin content was measured by assessing the difference in enzymatic activity of medullary homogenates before and after trypsin activation of prorenin. Trypsinization caused no change in control renin activity but a 5-fold increase in diabetes. Studies on a CD cell line (M1) showed a 22-fold increase in renin activity after trypsinization and a further 35-fold increase with Ang II treatment. Therefore, prorenin significantly contributes to baseline CD renin. Diabetes, possibly via Ang II, greatly stimulates CD prorenin and causes hyperplasia of renin-producing connecting segments. These novel findings suggest that, in a rat model of diabetes, prorenin content and release from the CD may be more important than the juxtaglomerular apparatus in contrast to the existing paradigm.
authors.affiliation: Department of Physiology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jung J
authors.initials: JJ
authors.lastname: Kang
authors.forename: Ildikó
authors.initials: I
authors.lastname: Toma
authors.forename: Arnold
authors.initials: A
authors.lastname: Sipos
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Meer
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Vargas
authors.forename: János
authors.initials: J
authors.lastname: Peti-Peterdi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004195:Disease Models, Animal; D006977:Hypertension, Renal / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D011796:Quinacrine; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014357:Trypsin; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C437965:olmesartan; D014357:Trypsin; D012083:Renin; D011796:Quinacrine