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Induction monotherapy with sirolimus has selected beneficial effects on glomerular and tubulointersititial injury in nephrotoxic serum nephritis

Authors Succar L, Lai-Kwon J, Nikolic-Paterson DJ, Rangan G

Received 17 March 2014

Accepted for publication 12 April 2014

Published 18 July 2014 Volume 2014:7 Pages 303—313


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Lena Succar,1 Julia Lai-Kwon,1 David J Nikolic-Paterson,2 Gopala K Rangan1

1Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, NSW, Australia; 2Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia

Background: The study aimed to test the hypothesis that therapeutic treatment with a mammalian target of rapamycin complex 1 inhibitor reduces renal cell proliferation and attenuates glomerular and tubulointerstitial injury in the early phase of nephrotoxic serum nephritis (NSN) in rats.
Methods: Male Wistar-Kyoto rats received a single tail-vein injection of sheep anti-rat glomerular basement membrane serum (day 0) and were treated with vehicle or sirolimus (0.25 mg/kg/day by subcutaneous injection) from day 1 until day 14.
Results: Treatment with sirolimus attenuated kidney enlargement by 41% (P<0.05), improved endogenous creatinine clearance by 50% (P<0.05), and reduced glomerular and tubulointerstitial cell proliferation by 53% and 70%, respectively, (P<0.05 compared to vehicle) in rats with NSN. In glomeruli, sirolimus reduced segmental fibrinoid necrosis by 69%, autologous rat immunoglobulin G deposition, glomerular capillary tuft enlargement, and periglomerular myofibroblast (α-smooth muscle actin-positive cells) accumulation (all P<0.05) but did not significantly affect glomerular crescent formation (P=0.15), macrophage accumulation (P=0.25), or the progression of proteinuria. In contrast, sirolimus preserved tubulointerstitial structure and attenuated all markers of injury (interstitial ED-1- and α-smooth muscle actin-positive cells and tubular vimentin expression; all P<0.05). By immunohistochemistry and Western blot analysis, sirolimus reduced the glomerular and tubulointerstitial expression of phosphorylated (Ser 235/236) S6-ribosomal protein (P<0.05).
Conclusion: Induction monotherapy with sirolimus suppressed target of rapamycin complex 1 activation, renal cell proliferation, and injury during the early stages of rodent NSN, but the degree of histological protection was more consistent in the tubulointerstitium than the glomerular compartment.

Keywords: glomerulonephritis, proliferation, crescentic, rapamycin, inflammation, kidney

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