Fluoride potentiates tubulointerstitial nephropathy caused by unilateral ureteral obstruction

Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments

“…The UUO-obstructed kidney (UUO-OK) is characterized by tubular dilation, interstitial expansion, loss of proximal tubular mass, hypertrophy, hydronephrosis, infiltration of leukocytes, tubular epithelial cell death and presence of fibroblasts. These alterations are a result of molecular processes such as hemodynamic change by mechanical stretching, epithelial tubular cell apoptosis, oxidative stress and inflammation; which altogether lead to progressive renal tubulointerstitial fibrosis [2,4,10,11,12]. A summary of the events in UUO is shown in Figure 1.…”

“…Such migration starts from day one of UUO and lasts throughout UUO [5]. In the UUO model, macrophages are accumulated in the renal cortex and promote inflammation [10]. The area that attracts the infiltrating macrophages is marked by the presence of adhesion molecules such as selectins [3].…”

“…For instance, at day 21 of UUO, no significant pathological changes were observed in kidney glomeruli [39]. Moreover, there is a strong correlation between progressive tubular epithelial cell death with the progression of fibrosis [2] and more severe renal tubulointerstitial fibrosis is observed in the renal cortex [10]. In rodents, the fibrosis can be more severe in neonates than in adult animals [2].…”

“…Histological staining techniques have shown that, in the UUO-OKs, there is severe structural damage, a decreased number of tubules, tubular atrophy, dilated tubules, cystic dilatation, infiltration of inflammatory cells, tubular epithelial cell apoptosis, tubulointerstitial fibrosis and accumulation of ECM [1,10,17,20,35]. The tubular lumen area has been measured to increase 5-fold in mice with UUO [32].…”

“…There are two types of macrophages: M1 (anti-ED3 or CD169) and M2 (anti-ED2 or CD163): M1 macrophages (the classically-activated macrophages that promote inflammation and apoptosis) become active as the initial line of defense and invade the renal cortex of the UUO-OK. Second, to counteract the increase in M1 macrophages, M2 macrophages (the alternatively-activated macrophages that promote cell survival and fibrogenesis) invade the inflammation site to prevent further inflammation. The increase in M2 macrophages produces an increment in the levels of TGF-β 1 , which results in the induction of fibrosis [5,10]. Significant correlations have been observed when comparing the fibrotic area and the collagen I-positive area with the number of M2 macrophages in the UUO-OKs [10].…”