title: Multiphoton imaging of the glomerular permeability of angiotensinogen.
abstract: Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration.
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: James L
authors.initials: JL
authors.lastname: Burford
authors.forename: Haykanush
authors.initials: H
authors.lastname: Gevorgyan
authors.forename: Saskia
authors.initials: S
authors.lastname: Seidel
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
mesh_terms: D000808:Angiotensinogen / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D000818:Animals; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D010539:Permeability; D051381:Rats; D011920:Rats, Inbred WF; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: C534931:AGT protein, human; C534933:Agt protein, rat; D000808:Angiotensinogen