title: Induction monotherapy with sirolimus has selected beneficial effects on glomerular and tubulointersititial injury in nephrotoxic serum nephritis.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Lena
authors: L
authors: Succar
authors: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Julia
authors: J
authors: Lai-Kwon
authors: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia.
authors: David J
authors: DJ
authors: Nikolic-Paterson
authors: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Gopala K
authors: GK
authors: Rangan
keywords: crescentic; glomerulonephritis; inflammation; kidney; proliferation; rapamycin