Medizinische Universität Graz - Research portal
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SHR Neuro Cancer Cardio Lipid Metab Microb
Kirsch, AH; Riegelbauer, V; Tagwerker, A; Rudnicki, M; Rosenkranz, AR; Eller, K.
The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response.
Am J Physiol Renal Physiol. 2012; 303(4):F569-F575
Doi: 10.1152/ajprenal.00180.2012
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- Leading authors Med Uni Graz
- Eller Kathrin
- Kirsch Alexander
- Co-authors Med Uni Graz
- Rosenkranz Alexander
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- Abstract:
- Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4(+) T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Antigens, CD31 - genetics
- Gene Expression Regulation - drug effects
- Immunity, Innate - drug effects
- Inflammation Mediators - metabolism
- Male -
- Membrane Proteins - genetics
- Mice -
- Mice, Inbred C57BL -
- Nephritis - chemically induced
- Proteinuria - metabolism
- RNA, Messenger -
- Sirolimus - pharmacology
- TOR Serine-Threonine Kinases - antagonists & inhibitors
- Vascular Endothelial Growth Factor A - genetics
- Find related publications in this database (Keywords)
- mammalian target of rapamycin inhibition
- rapamycin
- glomerulonephritis
- proteinuria