Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. May 6, 2016; 5(3): 288-299
Published online May 6, 2016. doi: 10.5527/wjn.v5.i3.288
C5b-9 does not mediate tubulointerstitial injury in experimental acute glomerular disease characterized by selective proteinuria
Gopala K Rangan
Gopala K Rangan, Westmead Institute for Medical Research Level 5, Centre for Transplant and Renal Research, Sydney, NSW 2145, Australia
Gopala K Rangan, Department of Renal Medicine, Westmead Hospital, Sydney, NSW 2145, Australia
Author contributions: GR conceived the idea for the study; undertook laboratory work, data collection, data analysis and interpretation, prepared and drafted the manuscript.
Supported by The United States National Institutes of Health (Nos. DK34198 and DK07467) to Dr. Couser; The Don Jacquot Fellowship (Australian and New Zealand Society of Nephrology Travelling Fellowship ), The BJ Amos Travelling Fellowships (Westmead Hospital), The Medical Research Fund of Western Australia, The Fremantle Hospital Medical Research Foundation and The National Health and Medical Research Council (No. 230500) to Dr. Rangan.
Institutional review board statement: The study was reviewed and approved by the Animal Use Care Committee of the University of Washington and the Westmead Hospital Animal Ethics Committee, Western Sydney Local Health District, Westmead, Sydney, Australia (Protocol No. 135.02-08).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Use Care Committee of the University of Washington and Westmead Hospital Animal Ethics Committee (Protocol No. 135.12-08).
Conflict-of-interest statement: The author has no conflict of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Gopala K Rangan, MB BS, PhD, FRACP, Westmead Institute for Medical Research Level 5, Centre for Transplant and Renal Research, 176 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia. g.rangan@sydney.edu.au
Telephone: +61-2-86273502 Fax: +61-2-94751146
Received: October 26, 2015
Peer-review started: November 3, 2015
First decision: November 30, 2015
Revised: January 12, 2016
Accepted: March 9, 2016
Article in press: March 14, 2016
Published online: May 6, 2016
Abstract

AIM: To determine whether complement membrane attack complex (C5b-9) has a pathogenic role in tubulointerstitial injury in a renal disease model characterized by acute highly selective proteinuria.

METHODS: Protein-overload nephropathy (PON) was induced in adult female Piebald-Viral-Glaxo rats with or without complement C6 deficiency (C6- and C6+) by daily intraperitoneal injections of bovine serum albumin (BSA, 2 g/d), and examined on days 2, 4 and 8.

RESULTS: Groups with PON developed equivalent levels of heavy proteinuria within 24 h of BSA injection. In C6+ rats with PON, the tubulointerstitial expression of C5b-9 was increased and localized predominantly to the basolateral surface of tubular epithelial cells (TECs), whereas it was undetectable in C6- animals. TEC proliferation (as assessed by the number of BrdU+ cells) increased by more than 50-fold in PON, peaking on day 2 and declining on days 4 to 8. There was a trend for a reduction in the number of BrdU+ TECs on day 4 in the C6- PON group (P = 0.10 compared to C6+) but not at any other time-point. Kidney enlargement, TEC apoptosis (TUNEL+ cells) and markers of tubular injury (tubule dilatation, loss of TEC height, protein cast formation) were not altered by C6 deficiency in PON. Interstitial monocyte (ED-1+ cell) accumulation was partially reduced in C6- animals with PON on day 4 (P = 0.01) but there was no change in myofibroblast accumulation.

CONCLUSION: These data suggest that C5b-9 does not mediate tubulointerstitial injury in acute glomerular diseases characterized by selective proteinuria.

Keywords: Apoptosis, Proliferation, Tubulointerstitial, Proteinuria, C5b-9, Complement, Rats

Core tip: The intra-renal assembly of the complement membrane attack complex (C5b-9) in the tubular lumen may be one of the principal mediators of chronic tubulointerstitial damage in nephrotic glomerular disease. This study shows that in an acute glomerular disease model (protein overload nephropathy) characterized by the rapid onset of highly selective proteinuria, C5b-9 does not mediate early tubulointerstitial injury. This may be due to the low luminal formation of C5b-9 in this model, and suggests that other factors, such as the filtration of albumin, growth factors and/or microtubular protein-cast obstruction, are more important in the pathogenesis of tubulointerstitial injury under these circumstances.