Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Hochegger, Kathrin; Jansky, Gerhard L.; Soleiman, Afschin; Wolf, Anna Maria; Tagwerker, Andrea; Seger, Christoph; Griesmacher, Andrea; Mayer, Gert; Rosenkranz, Alexander R.

doi:10.1681/asn.2007121375

Cited by 31 publications

(37 citation statements)

References 32 publications

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“…50,51 However, to our knowledge, there has been only one report on the role of mTOR activation in anti-GBM nephritis showing that pretreatment of rapamycin protected glomerular injury through affecting T-and B-cell activation. 52 However, the typical glomerular change in their animal model was severe mesangial expansion and not CGN. Role of LAT2 and mTORC1 in crescentic formation R Kurayama et al A major finding in the present study is that activation of mTORC1 pathway commenced in the glomerular PECs and podocytes before apparent crescent formation and increased in the crescent lesion itself of CGN (Figure 3a).…”

Section: Discussionmentioning

confidence: 97%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Discussionmentioning

confidence: 97%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…On the one hand, immune initiation and regulation takes place in the draining lymph nodes, and on the other hand, the immune effector phase is located in the kidneys. Based on previous observations of our group, we suggested that mainly the immune regulation taking place in the secondary lymphoid organs 14,16,24 can protect mice from NTS, whereas immune regulations in the kidney may only affect the severity of the disease. Here, we only detected significantly increased Tim3 expression in kidneys of mice subjected to NTS, whereas no significant increase was found in the draining lymph nodes.…”

Section: Tim3 and Nephrotoxic Serum Nephritis 1721mentioning

confidence: 84%

“…Because the B cell response is of relevance in our model of NTS, 24 we tested for putative differences of mouse-antirabbit IgG titers as a function of anti-Tim3 treatment. Seven days after induction of NTS, no difference in the whole immunoglobulin and immunoglobulin subclasses IgG1 and IgG3 concentrations were found in mice treated with either a Tim3-blocking antibody or the respective isotype control (Table 2).…”

Section: Effects Of Tim3 Blockade On Local B and T Cell Responses In Ntsmentioning

confidence: 99%

“…As this NTS model is a T H -1 dependent, in which T H -17 cells might also be of importance, 24 we next studied T cell function. Only very few CD4 ϩ T cells were found to infiltrate kidneys 7 days after induction of NTS, but significantly higher numbers of CD4 ϩ T cells were found in anti-Tim3-treated mice as compared with isotype control-treated animals ( Figure 5A).…”

Section: Effects Of Tim3 Blockade On Local B and T Cell Responses In Ntsmentioning

confidence: 99%

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Tim3 Is Upregulated and Protective in Nephrotoxic Serum Nephritis

Schroll

Eller

Huber

et al. 2010

The American Journal of Pathology

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T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (T H ) that negatively regulates T H -type 1(T H -1) responses. Because blockade of Tim3 aggravates disease activity in T H -1-dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the T H -1-dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3-expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4 ؉ T cells rather than CD8؉ cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3-treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease.

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“…In experimental studies it was proposed that a decrease of vascular endothelial growth factor and/or an increase in proinflammatory cytokines such as interleukin-6 might be responsible for the pathologies observed. [6][7][8] Rapamycininduced proteinuria is not only observed in renal transplant patients, but was recently shown also in long-term cardiac transplant patients. 9 In patients after SCT data on the clinical efficacy of rapamycin is scarce.…”

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confidence: 93%