The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response

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.

Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

“…Interestingly, increased proteinuria has been observed with chronic treatment with everolimus, a derivative of rapamycin 32, 33 . In the present study, rapamycin treated rats exhibited 5-fold reduction of daily albumin excretion which was an even greater response than that found in SS CD247−/− rats 30 and tacrolimus treated rats 4 , which exhibited only a 3-fold reduction of daily albumin excretion.…”

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…In many, though not all, situations the activation of innate immune cells leads to inflammation, which in controlled settings is host protective and can set the scene for adaptive immune response development. The administration of rapamycin in various inflammatory settings in vivo has shown that mTORC1 can either promote or inhibit inflammation, depending on the setting (Cejka et al, 2010; Kirsch et al, 2012), illustrating that the role of mTOR in innate immunity is complex and context dependent. In this section we will discuss the roles of mTORC1 and mTORC2 in the biology of innate immune cells.…”

Macrophage metabolism: a wound‐healing perspective

“…mTOR is present in two complexes, mTORC1 and mTORC2, which have distinct structure and function. In macrophages, mTORC1 has been shown to either promote or inhibit inflammation in a context‐dependent manner . In alternatively activated macrophages, mTORC1 was found to increase glucose metabolism and flux of carbon into the TCA .…”