David J Nikolic-Paterson

Publications (165) View all

• Article: The role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis.

  Yingjie Han, Frank Y Ma, Greg H Tesch, Carl L Manthey, David J Nikolic-Paterson
  [show abstract] [hide abstract]
  ABSTRACT: The ability of macrophages to cause acute inflammatory glomerular injury is well established; however, the role of macrophages in the fibrotic phase of chronic kidney disease remains poorly understood. This study examined the role of macrophages in the fibrotic phase (days 14 to 35) of established crescentic glomerulonephritis. Nephrotoxic serum nephritis (NTN) was induced in groups of 8 WKY rats which were given a selective c-fms kinase inhibitor, fms-I, or vehicle alone from day 14 until being killed on day 35. Rats killed on day 14 NTN had pronounced macrophage infiltration with glomerular damage, fibrocellular crescents in 50% of glomeruli, tubulointerstitial damage, heavy proteinuria and renal dysfunction. Glomerulosclerosis was more severe by day 35 in vehicle treated rats, as was periglomerular and interstitial fibrosis, while proteinuria and renal dysfunction continued unabated and some parameters of tubular damage worsened. During the day 14 to 35 period, glomerular and interstitial macrophage infiltrate decreased with an apparent change from a pro-inflammatory M1 phenotype to an alternatively activated M2 phenotype. Treatment with fms-I over day 14 to 35 selectively reduced blood monocyte numbers and abrogated glomerular and interstitial macrophage infiltration. This resulted in improved renal function, significantly reduced glomerular and interstitial fibrosis, and protection against further peritubular capillary loss. However, sustained proteinuria, tubular damage and interstitial T cell infiltration and activation were unaffected. In conclusion, this study demonstrates that macrophages contribute to renal dysfunction and tissue damage in established crescentic glomerulonephritis as it progresses from the acute inflammatory to a chronic fibrotic phase.
  AJP Renal Physiology 02/2013; · 4.42 Impact Factor
• Article: Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction.

  Shaun A Summers, Poh-Yi Gan, Lakshi Dewage, Frank T Ma, Joshua D Ooi, Kim M O'Sullivan, David J Nikolic-Paterson, A Richard Kitching, Stephen R Holdsworth
  [show abstract] [hide abstract]
  ABSTRACT: Progressive renal fibrosis is the final common pathway leading to renal failure irrespective of the initiating cause. Clinical studies of renal fibrosis found that prominent mast cell accumulation correlated with worse outcomes. Mast cells are pluripotent innate immune cells that synthesize and secrete profibrotic mediators. Here we use mast cell-deficient (Kit(W-sh/W-sh)) mice to define a functional pathogenic role for these cells in the development of renal fibrosis. Intrarenal collagen deposition was significantly decreased in mast cell-deficient compared to wild-type mice 7 and 14 days after unilateral ureteric obstruction. The intrarenal expression of mRNAs for transforming growth factor-β, α-smooth muscle actin, chemokines, and renal macrophages and CD4(+) T cells were also decreased in mast cell-deficient mice. Reconstitution of the mast cell population in mast cell-deficient mice with wild-type bone marrow-derived mast cells restored the pattern and intensity of renal fibrosis to levels seen in wild-type mice following ureteric ligation. Interestingly, the mast cells were recruited, activated, and degranulated within 6 h of ureteric ligation. A mast cell stabilizer that impairs degranulation, disodium chromoglycate, significantly attenuated renal fibrosis following ureteric ligation in wild-type mice. Thus, mast cells promote renal fibrosis and their targeting may offer therapeutic potential in the treatment of renal fibrosis.Kidney International advance online publication, 6 June 2012; doi:10.1038/ki.2012.211.
  Kidney International 06/2012; · 6.61 Impact Factor
• Source

  Available from: Jiangning Song

  Article: Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation.

  Xinli Qu, Xueming Zhang, Jun Yao, Jiangning Song, David J Nikolic-Paterson, Jinhua Li
  [show abstract] [hide abstract]
  ABSTRACT: Resolvin E1 (RvE1) is a naturally occurring lipid-derived mediator generated during the resolution of inflammation. The anti-inflammatory effects of RvE1 have been demonstrated in a variety of disease settings; however, it is unknown whether RvE1 may also exert direct anti-fibrotic effects. We examined the potential anti-fibrotic actions of RvE1 in the mouse obstructed kidney - a model in which tissue fibrosis is driven by unilateral ureteric obstruction (UUO) - an irreversible, non-immune insult. Administration of RvE1 (300ng/day) to mice significantly reduced accumulation of α-smooth muscle actin (SMA)+ myofibroblasts and the deposition of collagen IV on day 6 after UUO. This protective effect was associated with a marked reduction of myofibroblast proliferation on days 2, 4 and 6 after UUO. RvE1 treatment also inhibited production of the major fibroblast mitogen, platelet-derived growth factor-BB (PDGF-BB), in the obstructed kidney. Acute resolvin treatment over days 2 to 4 after UUO also had a profound inhibitory effect upon myofibroblast proliferation without affecting the PDGF expression, suggesting a direct effect upon fibroblast proliferation. In vitro studies established that RvE1 can directly inhibit PDGF-BB-induced proliferation in primary mouse fibroblasts. RvE1 induced transient, but not sustained activation of the pro-proliferative ERK and AKT signalling pathways. Of note, RvE1 inhibited the sustained activation of ERK and AKT pathways seen in response to PDGF stimulation, thereby preventing up-regulation of molecules required for progression through the cell cycle (c-Myc, cyclin D) and down-regulation of inhibitors of cell cycle progression (p21 cip1). Finally, siRNA-based knock-down studies showed that the RvE1 receptor, ChemR23, is required for the anti-proliferative actions of RvE1 in cultured fibroblasts. In conclusion, this study demonstrates that RvE1 can inhibit fibroblast proliferation in vivo and in vitro, identifying RvE1 as a novel anti-fibrotic therapy. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
  The Journal of Pathology 05/2012; · 6.32 Impact Factor
• Article: Macrophage infiltration and renal damage are independent of matrix metalloproteinase 12 in the obstructed kidney.

  Abu P Abraham, Frank Y Ma, William R Mulley, Elyce Ozols, David J Nikolic-Paterson
  [show abstract] [hide abstract]
  ABSTRACT: To determine whether matrix metalloproteinase-12 (MMP-12) plays a functional role in renal interstitial macrophage accumulation, interstitial fibrosis or tubular apoptosis in the unilateral ureteric obstruction (UUO) model. MMP-12 is an enzyme that can cleave a number of extracellular matrix proteins and plays a role in macrophage-mediated injury in experimental models of emphysema and antibody-dependent glomerular disease. Macrophages are thought to promote renal fibrosis and tubular damage in the obstructed kidney. Furthermore, upregulation of MMP-12 expression by infiltrating macrophages in the obstructed kidney has been described, but the potential role of MMP-12 in renal injury induced by this non-immune insult is unknown. Groups of eight MMP-12 gene deficient (MMP-12(-/-)) and wild type (WT) C57BL/6J mice were killed 3, 7 or 14 days after UUO. Analysis of three different lineage markers found no difference in the degree of interstitial macrophage accumulation between MMP-12(-/-) and WT UUO groups at any time point. Examination of renal fibrosis by total collagen staining, α-SMA + myofibroblast accumulation, and TGF-β1, PAI-1 and collagen IV mRNA levels showed no difference between MMP-12(-/-) and WT UUO groups. Finally, tubular damage (KIM-1 levels) and tubular apoptosis (cleaved caspase-3) in the obstructed kidney was not affected by MMP-12 gene deletion. In contrast to lung injury and antibody-dependent glomerular injury, MMP-12 is not required for renal interstitial macrophage accumulation, interstitial fibrosis or tubular damage in the obstructed kidney.
  Nephrology 01/2012; 17(4):322-9. · 1.31 Impact Factor
• Article: Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.

  Yuji Nozaki, David J Nikolic-Paterson, Sarah L Snelgrove, Hisaya Akiba, Hideo Yagita, Stephen R Holdsworth, A Richard Kitching
  [show abstract] [hide abstract]
  ABSTRACT: The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4(+) T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim-1 in experimental T-cell-mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4(+) cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3(+) cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis.
  Kidney International 12/2011; 81(9):844-55. · 6.61 Impact Factor