The focal segmental glomerulosclerosis (FSGS) is a complex renal disease characterized by different kind of lesions with distinct progression and responses to treatments. The search for a representative experimental model is fundamental to deep understand the course of disease. Balb/c mice is the classic strain used for FSGS experimental model, however others strain as C57/black 6 was also adapted presenting similar dysfunctions to classic model . Here, we were innovative and by first time, it was adapted a heterogeneous mouse strain for experimental FSGS, Swiss line, that importantly mimic the heterogenicity of FSGS patients, providing tools for more effective investigations [2, 4–6, 11, 12, 32–36]. We observed in our novel experimental model that treatment with DOX caused typical FSGS signs (higher proteinuria and weight loss) in mice representing a new FSGS model in the literature, since the model of DOX nephropathy has not been yet developed in this lineage yet.
Considering that FSGS was adapted in our Swiss mice, we decided to investigate the participation of STAT-3 in our model of nephropathy induced by DOX. Proteinuria, especially albuminuria, is one of the main signs found in the model of DOX-induced nephropathy. Albuminuria is due to alterations in the glomerular filtration barrier and oxidative damage in the podocytes caused by DOX  [9, 37]. In our study, significant albuminuria was observed in animals injected with DOX and treatment with STATTIC significantly decreased not only albuminuria but also glycosuria in these animals. In addition, we detected that STATTIC modulated STAT-3 levels and was possible to pointed out the STAT-3 signal molecule as an important marker for experimental FSGS progression .
In order to evaluated the dynamic of STAT-3 signaling, we searched for pro-inflammatory cytokines present in this pathway and that could be altered in our model. Initially, we verified elevated IL-6 levels in DOX-treated animals. In contrast, the inhibition of STAT-3 signal caused a dramatic reduction in its expression. Interleukin-6 has a pleiotropic action on several biological functions and can be secreted by many cell types through stimuli such as infection, inflammation or cancer . For instance, The secretion of IL-6 by monocytes and macrophages following the activation of Toll-like receptors is especially important in cases of inflammation . Moreover, Hunter & Jones  emphasized that there is extensive literature showing that IL-6 modulates various aspects of the innate immune system, including hematopoiesis and neutrophil accumulation at sites of infection or trauma. Thus, it is possible to infer that DOX causes inflammation, with a possible infiltration of macrophages, which in our study can be represented by elevated index of inflammatory cells in renal tissues. These cells are responsible to increase of IL-6 mRNA expression that is frequently observed in patients with primary FSGS associated with cutaneous and systemic plasmacytosis , beyond other nephropathies, such as IgA nephropathy . In line with this, it was also detected significant differences in IL-6 receptor gene (IL-6R) expression between the DOX-injected and STATTIC-treated animals. The blocked of IL-6/IL-6R axis by inhibition of STAT-3 suggests a possible modulation of inflammation with consequent preservation of renal tissue and function. Furthermore, we observed that the treatment with STAT-3 inhibitor resulted in great increase of cytokine signaling suppressor type 3 (SOCS-3). SOCS-3 down regulates the JAK/STAT signal by binding simultaneously to glycoprotein Gp130 (one subunit of the type I cytokine receptor within the IL-6 receptor family) and JAK (a non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway), blocking binding to the substrate . Thus, these findings can be interpreted as a cellular response for modulate inflammation caused by STAT-3 activation.
Finally, is reported that renal inflammation can trigger renal fibrosis cascade and impair kidney function . Then is expected that DOX-mediated inflammation may promote fibrosis in FSGS experimental model. According to this we observed that DOX-administrated mice demonstrated consistent signs of tubulointerstitial fibrosis and tubular necrosis which did not were observed in control animals e STATTIC-treated group. Tao et al  using microscopic and transcriptomic evidences also identified glomerular and tubulointerstitial STAT-3 activation in renal biopsy of FSGS patients. Additionally, Bienaimè  yet demonstrated an important role for STAT-3 in tubulointerstitial communication during chronic kidney disease. The authors reported that STAT-3 activation promotes accumulation of interstitial matrix and fibroblasts, leading to increasing of tubulointerstitial fibrosis, while the STAT-3 inactivation causes decrease in tubulointerstitial fibrosis. Thus, our results indicate that STAT-3 pathway possess an important role in experimental FSGS induced by DOX and may be an important molecule to be investigated in further studies.