Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN.
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.
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Partab
P
Rai
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Rivka
R
Lederman
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Shabirul
S
Haque
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Shabina
S
Rehman
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Viki
V
Kumar
University of Texas Health Science Center, San Antonio, TX, United States.
Kavithalakshmi
K
Sataranatrajan
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States.
Ashwani
A
Malhotra
University of Texas Health Science Center, San Antonio, TX, United States.
Balakuntalam S
BS
Kasinath
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, New York, NY, United States. Electronic address: psinghal@nshs.edu.
Pravin C
PC
Singhal
D016263:AIDS-Associated Nephropathy / Q000235:genetics*; D000577:Amides / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers / Q000378:metabolism; D000818:Animals; D005650:Fumarates / Q000494:pharmacology; D006678:HIV; D007674:Kidney Diseases / Q000662:veterinary / Q000821:virology*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D005650:Fumarates; D044139:Receptor, Angiotensin, Type 2; C446481:aliskiren; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D019808:Losartan
Angiotensin II type 1 receptor; Angiotensin II type II receptor; Renal proximal tubular cells; Renin