International Journal of Nephrology 3 Hyperglycemia PDGF Adiponectin ↓ AMPK ↑ AMPK Stimulates ↑ mTOR Inhibits Cell growth and proliferation Glomerular hypertrophy Matrix expansion, mesangial hypertrophy Figure 1: Hyperglycemia and PDGF stimulate mTOR, which in turn contribute to the nuclear translation of mRNAs necessary for cell growth and proliferation, clinically evident as hematuria, proteinuria, and glomerular ﬁltration rate alterations. this dose is below that used to produce clinically immuno- suppressive eﬀects (4.5–14 ng/mL), but could also minimize other potential adverse drug eﬀects [37]. 4. mTOR Inhibition: Low versus High Dose In experimental studies, diﬀerent doses of mTORi may play opposite eﬀects on mesangial expansion. This may appear to be particularly true with respect to mesangioproliferative glomerulonephritis. In this respect, low-dose rapamycin (2.5 mg/kg−1/body weight−1 in rats) confers antiproteinuric eﬀects in a chronic model of progressive mesangioprolifera- tive nephropathy, that is, anti-thy1-induced glomeruloscle- rosis in the rat [36]. Brieﬂy, rapamycin remarkably limits the progressive course of chronic anti-thy1 antibody-induced renal disease towards glomerulosclerosis, tubulointerstitial ﬁbrosis, and renal insuﬃciency. Renoprotection by low-dose rapamycin presents beneﬁcial eﬀects on a number of key pathways of renal disease progression, that is, proteinuria, renal matrix protein accumulation, cell proliferation, and leukocyte inﬁltration [12–15, 36]. Moreover, the beneﬁcial eﬀects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, that is, hypertensive 5/6 nephrectomy, diabetic nephropathy, hyper- trophy following unilateral nephrectomy, tubulointerstitial ﬁbrosis due to uretheral obstruction or nephrotic syndrome, and polycystic kidney disease, but not chronic transplant glomerulopathy [38–43]. Since these experimental studies represent the vast majority of human chronic kidney disease, their ﬁndings together imply that mTOR signaling acts as a rather common key pathway in the progression of renal disease. Furthermore, these studies suggest that inhibition of mTOR might be a novel, generally eﬀective therapeutic approach to chronic kidney disease. However, the latter option may also apply to early preventive treatment, since this represents generally the timing of mTOR inhibition in experimental rat studies. However, the outcome of mTOR inhibition in anti-thy1-induced glomerulosclerosis contrasts with the one previously reported in anti-thy1-induced acute glomerulonephritis [44, 45]. In the latter, the mTOR inhibitor everolimus before or during the early marked mesangial cell proliferation turned out to be detrimen- tal, manifesting aggravation of proteinuria, impaired self- healing, increased uremic mortality, and persistent glomeru- lar ﬁbrotic changes. These eﬀects were observed both with high- and low-dose everolimus [44]. The studies in anti-thy1 acute and chronic renal disease unanimously indicate that unaﬀected mTOR signaling is critical for the very early and marked mesangial cell proliferation and subsequent normal glomerular repair of acute anti-thy1 glomerulonephritis [36, 44, 45]. In the further course of the disease, inhibition of mTOR even acts beneﬁcially and prevents chronic disease progression [36]. Daniel et al. [45] reported renoprotective eﬀect of sirolimus in experimental mesangioproliferative glomerulonephritis. Application of everolimus as late treat- ment for 14 weeks attenuated proteinuria and the time course of chronic anti-Thy1 nephritis in the rat, through reduction in vascular endothelial growth factor VEGF and TGF-β1expression [38]. VEGF is a potent mitogen expressed in podocytes and tubular cells that normally facilitates both glomerular and interstitial endothelial proliferation and angiogenesis [38, 46, 47]. Outlined by Schrijvers et al., the role of VEGF in normal renal physiology is essentially unknown [48]. However, VEGF and its receptors are upregulated in experimental animals and humans with type 1 and 2 diabetes and mesangioproliferative glomerulonephritis as IgAN [48– 50]. Overexpression of VEGF-A leads to glomerular collapse, proteinuria, and end-stage renal disease in mice [50, 51]. In subjects with early IgAN, expression of VEGF is upregulated [52]. Some VEGF polymorphisms may be associated with the increased risk of renal progression in patients with IgA nephropathy [50]. Finally, VEGF expression is genetically regulated via the mTOR pathway [53, 54], which is in turn well known to be inhibited by both sirolimus and everolimus. In contrast to Daniel et al. [44], Ramadan et al. have shown that either early or late low (20 mg/L) but not high doses (100 mg/L) of everolimus attenuated the loss of the slit diaphragm proteins nephrin and podocin in adriamycin- induced nephrotic syndrome (an experimental nephropathy that mimics minimal change disease), suggesting that the antiproteinuric eﬀect of this agent at the therapeutic dose is due to preservation of nephrin and podocin. Speciﬁcally, chronic administration of everolimus at high therapeutic doses to normal rats did not induce renal injury as expressed by the lack of adverse eﬀects on glomerular nephrin/podocin abundance. However, the authors speculate that this high- dose eﬀect may be due to a decline of glomerular ﬁltration rate and to the hypoalbuminemia seen in these rats [24]. The eﬃcacy of mTORi in mesangioproliferative glomer- ulonephritis is limited. These potential beneﬁcial results achieved in experimental studies are now expanding to- wards a progressive model of human mesangioproliferative nephropathy, an important cause of end-stage kidney disease