The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin.
BACKGROUND
The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far.


METHODS
In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis.


RESULTS
We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation.


CONCLUSIONS
These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.
Stylianou
Kostas
K
Department of Nephrology, Heraklion University Hospital, and Laboratory of Electron Microscopy, University of Crete, Crete, Greece. kstylianu@gmail.com
Petrakis
Ioannis
I
Mavroeidi
Vasiliki
V
Stratakis
Stavros
S
Vardaki
Eleftheria
E
Perakis
Kostas
K
Stratigis
Spyros
S
Passam
Andreas
A
Papadogiorgaki
Eva
E
Giannakakis
Kostas
K
Nakopoulou
Lydia
L
Daphnis
Eugene
E
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008181:Lupus Nephritis / Q000378:metabolism*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
D007166:Immunosuppressive Agents; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse