**1. Introduction**

Glomerulonephritis (GN) is a constellation of heterogenous renal diseases featured as a shared pathophysiology of immune mediated glomerular inflammation [1,2]. Some GN patients may benefit from specific immunosuppressive therapies and many others who are irresponsive to this type of managemen<sup>t</sup> eventually develop end stage renal disease (ESRD) [3–6]. Glomerulonephritis is one of the leading causes of ESRD and remains a medical challenge [7]. Implementation of interventions to

cure or prevent GN related deterioration is very important from both public health and economic aspects. Stem cells have the potential of self-renewal and the ability of immune modulation and as such, provide a potential therapeutic option to the unmet need of GN su fferers [8].

Mesenchymal stem cells (MSCs) have been shown to improve renal functions in animal GN models [8], and in some refractory human lupus nephritis studies [9–11]. In these studies, MSCs cross-talked with target organs by secreting growth factors, cytokines, and prostaglandins, which regulate anti-inflammation, anti-apoptosis, and anti-fibrosis e ffects and enhance cell proliferation, survival, and angiogenesis to repair injured tissue. These paracrine e ffects play a major role in MSC's therapeutic e ffect to the damaged kidney [2,8,12]. Additionally, increased oxidative stress contributes to the pathogenesis of mesangial proliferative GN and leads to renal dysfunction [13]. MSCs have been shown to possess anti-oxidative e ffects which help in the treatment of GN [14]. Strategies to enhance their anti-oxidative ability could promote the therapeutic e fficacy of MSCs [15]. However, compared with the anti-inflammatory and immune-modulatory e ffects, the mechanisms underlying the anti-oxidative e ffects are relatively unknown. Hypoxic preconditioning is a promising strategy to improve the e fficacy and stemness of MSC therapy, through preventing senescence, increasing di fferentiation e fficiency [16], and enhancing MSC homing [17]. There is surprisingly little knowledge about how hypoxic preconditioning a ffects the anti-oxidative therapeutic e ffects of MSCs. The present study aimed to investigate the anti-oxidative stress mechanisms involved in the use of locally intrarenal transplantation, for reduction of possible adverse e ffect, of normoxic MSCs and hypoxic-preconditioned mesenchymal stem cells (HMSCs) in the anti-thy1.1 GN rat model.
