Multiphoton Imaging of the Glomerular Permeability of... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Nakano, Daisuke*; Kobori, Hiroyuki*,†; Burford, James L.‡; Gevorgyan, Haykanush‡; Seidel, Saskia‡; Hitomi, Hirofumi*; Nishiyama, Akira*; Peti-Peterdi, Janos‡

* Department of Pharmacology, Kagawa University, Kagawa, Japan;

† Departments of Medicine and Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana; and

‡ Departments of Physiology and Biophysics and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California

Correspondence: Dr. Janos Peti-Peterdi, Department of Physiology and Biophysics and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, 1501 San Pablo Street, ZNI 335, Los Angeles, CA 90033. Email: [email protected]

Received January 24, 2012

Accepted July 10, 2012

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.