TY - JOUR
T1 - Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN
AU - Rai, Partab
AU - Lederman, Rivka
AU - Haque, Shabirul
AU - Rehman, Shabina
AU - Kumar, Viki
AU - Sataranatrajan, Kavithalakshmi
AU - Malhotra, Ashwani
AU - Kasinath, Balakuntalam S.
AU - Singhal, Pravin C.
N1 - Funding Information:
This work was supported by grants RO1DK084910 , RO1 DK083931 , and 1R01DK098074 (PCS) from the National Institutes of Health , Bethesda, MD.
PY - 2014/6
Y1 - 2014/6
N2 - Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R.
AB - Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R.
KW - Angiotensin II type 1 receptor
KW - Angiotensin II type II receptor
KW - Renal proximal tubular cells
KW - Renin
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U2 - 10.1016/j.yexmp.2014.04.004
DO - 10.1016/j.yexmp.2014.04.004
M3 - Article
C2 - 24768585
AN - SCOPUS:84899786977
SN - 0014-4800
VL - 96
SP - 431
EP - 437
JO - Experimental and Molecular Pathology
JF - Experimental and Molecular Pathology
IS - 3
ER -