2 proliferative glomerulonephritis, IgM glomerulonephritis, and C1q glomerulonephritis [10]. Progression in mesangioproliferative glomerulonephritis generally involves increasing proteinuria, pathological renal extracellular matrix protein accumulation, cell proliferation, and inﬂammatory cell inﬁltration [11–15]. Pharmacological treatment of progressive mesangioproliferative disease is practically limited to renin-angiotensin system inhibition using angiotensin-converting enzyme inhibitors or type 1 angiotensin receptor antagonists, which serves to decelerate but is generally not capable of halting the advance of the disease [2, 13, 15]. As recently remarked by Floege and Eitner, there are few randomized controlled trials for IgA nephropathy and very rarely do patient numbers exceed 200. Consequently, most guidelines relating to IgAN are based on a low-to-very-low level of evidence and, in many cases, suggestions cannot even be oﬀered. Thus, the majority of patients will continue to be treated based largely on opinion [16]. With respect to the other causes of mesangioprolifera- tive glomerulonephritis, in the absence of controlled trials, it is diﬃcult to determine the eﬃcacy of therapy [10]. Administration of various immunosuppressive regimes, containing steroids and cytotoxic/cytostatic drugs, is increas- ingly adopted. Since there is no ﬁnal agreement regarding the antiproteinuric eﬃcacy of these protocols, which also vary in diﬀerent disease states, and side eﬀects are important, the clinical eﬃcacy of new immunosuppressors is increasingly assessed [17–19]. Among these, the mammalian target of the rapamycin (mTOR) inhibitor family, which includes sirolimus and everolimus, is frequently used immuno- suppressant with proliferation signal inhibitors properties employed in nephrology [17–20]. However, serious side eﬀects including renal injury and proteinuria have been described during treatment with these drugs, in the setting of renal allograft nephropathy, human glomerulonephritis as well as in experimental kidney disease [19, 21–23]. Despite this, mTOR inhibition has been shown to be beneﬁcial in chronic mesangioproliferative nephropathy and to reduce proteinuria in an experimental anti-Thy1 nephri- tis (a chronic model of progressive mesangioproliferative nephropathy) and in focal segmental glomerulosclerosis [24]. Aberrant proliferation of mesangial cells is a common ﬁnding in a number of diseases that can lead to end-stage renal failure. A variety of initial insults, which may be metabolic (as in diabetic nephropathy) or immunological (as in IgA disease and lupus nephritis), can cause uncontrolled mesangial cell proliferation. This in turn causes an increase in extracellular matrix deposition, ultimately leading to glomerulosclerosis, with subsequent activation of common intermediate pathways, associated with increased synthesis and a release of growth factors, cytokines, chemokines, and oxidant species, which stimulate the further proliferation of mesangial cells and ﬁnally mediating the damage of the kidney parenchyma. It is important to understand the proliferation mechanism of mesangial cell in order to determine the key regulatory molecular pathways involved in the pathological response to injury and ultimately to identify potential targets for therapeutic intervention [25]. International Journal of Nephrology 2. Abnormal Cellular Mechanisms of Mesangial Proliferation in Mesangioproliferative Glomerulonephritis Platelet-derived growth factor (PDGF) has been recognized as a major mitogen and one of the most important growth factors, which mediates multiple cellular activities such as cell proliferation, hypertrophy, and extracellular matrix protein synthesis in various types of cells including mesangial cells, and plays an important role in the changes in glomerular morphology in diabetic nephropathy [25, 26] and mesangioproliferative glomerulonephritis, mainly IgAN [27] (Figure 1). In recent years, growing evidence suggests that adiponectin is also an important regulator of cell proliferation. The data about its inﬂuence on cell proliferation are conﬂicting. Some authors suggest that adiponectin stimulates endothelial cell growth and angio- genesis [28, 29], whereas others perceive it as a negative regulator of cell proliferation [30, 31]. Su et al. found that adiponectin inhibited PDGF-induced mesangial cell prolifer- ation. Mechanistic insights into this phenotype suggest that adiponectin attenuates PDGF-induced phosphorylation of mTOR via AMPK activation [25]. Interestingly, in a recent study it has been reported that in subjects with mesangial cell proliferation, as IgAN and diabetic nephropathy, there exists an increase of urinary adiponectin levels, which may partly result from enhanced ﬁltration of circulating adiponectin through the changes of glomerular permselectivity and intraglomerular hydraulic pressure [32]. 3. Regulation of mTOR The mammalian target of rapamycin plays a critical role in cell diﬀerentiation, migration, and survival [33–35]. mTOR is an intracellular serine/threonine kinase and a central component of a complex signaling network that is highly conserved in evolutionary terms and expressed ubiquitously throughout the cells of the body. mTOR is a component of two major intracellular signaling complexes (mTORC1 and mTORC2), that play diﬀerent roles downstream. mTORC1 is activated by growth factors and amino acids and controls cellular proliferation, promoting processes such as DNA translation, RNA transcription, ribosomal biogenesis, and cell cycle progression [35]. Inhibitors of mTOR, such as rapamycin or everolimus, bind to an intracellular cytoplas- matic receptor, the FK506-binding protein-12. The complex formed then interacts and disrupts mTOR function and leads to cell cycle arrest in the G1 phase. In addition to blocking cell proliferation, mTOR inhibitors have been found to be anti-inﬂammatory, antiﬁbrotic, antitumoral, and antifungal, which underscores the involvement of mTOR signaling in a wide range of cellular functions [33, 34, 36] (Figure 1). Thus, mTOR is essential for the proliferation of mesangial cells, as is the case of mesangioproliferative glomerulonephritis. In this regard, in vitro studies with mice mesangial cells under the eﬀect of diﬀerent concentrations of rapamycin showed that a remarkably low dose (0.01 ng/mL) inhibited both proliferation and type IV collagen production. However,