Sirolimus modulates HIVAN phenotype through inhibition of epithelial mesenchymal transition

Abstract

HIV-associated nephropathy (HIVAN) is characterized by proliferative phenotype in the form of collapsing glomerulopathy and microcystic dilatation of tubules. Recently, epithelial mesenchymal transition (EMT) of renal cells has been demonstrated to contribute to the pathogenesis of proliferative HIVAN phenotype. We hypothesized that sirolimus would modulate HIVAN phenotype by attenuating renal cell EMT. In the present study, we evaluated the effect of sirolimus on the development of renal cell EMT as well as on display of HIVAN phenotype in a mouse model of HIVAN (Tg26). Tg26 mice receiving normal saline (TgNS) showed enhanced proliferation of both glomerular and tubular cells when compared to control mice-receiving normal saline (CNS); on the other hand, Tg26 mice receiving sirolimus (TgS) showed attenuated renal cell proliferation when compared with TgNS. TgNS also showed increased number of α-SMA-, vimentin-, and FSP1- positive cells (glomerular as well as tubular) when compared with CNS; however, TgS showed reduced number of SMA, vimentin, and FSP1 +ve renal cells when compared to TgNS. Interestingly, sirolimus preserved renal epithelial cell expression of E-cadherin in TgS. Since sirolimus attenuated renal cell ZEB expression (a repressor of E-cadherin transcription), it appears that sirolimus may be attenuating renal cell EMT by preserving epithelial cell E-cadherin expression.

MicroRNAs in HIV-associated nephropathy (HIVAN)

“…Our previous studies have implicated several pathways that are involved in the pathogenesis of HIVAN, e.g., epithelial mesenchymal transition (EMT) was demonstrated to contribute to the proliferative phenotype of HIVAN (Yadav et al, 2010; Yadav et al, 2012). Tg26 mice showed enhanced renal tissue expression of ZEB2 and diminished expression of E-cadherin.…”

“…However, the exact mechanisms which contribute to the pathogenesis of HIVAN are not clear. Studies conducted in our laboratory demonstrated that epithelial-mesenchymal transition (EMT) in renal epithelial cells could contribute to the development of proliferative phenotype in HIV-1 transgenic mice (Tg26), the most commonly used mouse model of HIVAN (Kopp et al, 1992; Yadav et al, 2010; Yadav et al, 2012). In addition, mammalian target of rapamycin (mTOR) pathway was activated in HIVAN mice (Kumar et al, 2010; Rehman et al, 2012; Nicoletti et al, 2011).…”

Rapamycin-induced modulation of miRNA expression is associated with amelioration of HIV-associated nephropathy (HIVAN)

“…Recently, the role of mammalian target of rapamycin (mTOR) pathway has been demonstrated in the progression of in HIVAN [16]. Rapamycin, an inhibitor of mTOR pathway, not only inhibited the activation of the mTOR pathway but also attenuated the development of proliferative phenotype in HIVAN [35]. …”

“…These results indicate that miR-200 can be involved in the progression of HIVAN. In addition, rapamycin has been demonstrated to modulate HIV transcription as well as attenuation of the proliferative phenotype of HIVAN through inhibition of epithelial mesenchymal transition (EMT) in renal cells [35]. However, the contribution of rapamycin to miRNA expression in HIVAN and their potential role in the pathological processes has not been investigated to date.…”

Rapamycin-induced modulation of HIV gene transcription attenuates progression of HIVAN

“…One cannot change the genetic background; however, one can control the environmental factors and also modulate the host factors. Recently, the role of mammalian target of rapamycin (mTOR) pathway has been demonstrated in the development of proliferative phenotype in HIVAN (14); rapamycin (sirolimus) not only inhibited the activation of the mTOR pathway but also attenuated the development of proliferative phenotype in HIVAN (15). In addition, rapamycin has been reported to modulate HIV infection.…”