Inhibition of renin activity slows down the progression of HIV-associated nephropathy

Kumar, Dinesh; Plagov, Andrei; Yadav, Iti; Torri, Deepti D.; Sayeneni, Swapna; Sagar, Ankita; Rai, Partab; Adabala, Madhuri; Lederman, Rivka; Chandel, Nirupama; Ding, Guohua; Malhotra, Ashwani; Singhal, Pravin C.

doi:10.1152/ajprenal.00643.2011

Cited by 11 publications

(8 citation statements)

References 39 publications

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“…It has been reported that Tg26 displays slightly elevated BP compared with wild-type littermates and that ARBs can reduce BP in Tg26 mice. 37,38 In summary, we used a computational approach to predict a drug combination based on a database of drug-induced gene expression signatures. This tool helped us to predict potential drug combinations after incorporating the differential gene expression profiles from the disease model of HIVAN.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Zhong

Chen

Liu

et al. 2013

Journal of the American Society of Nephrology

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The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.

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Section: Discussionmentioning

confidence: 99%

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Zhong

Chen

Liu

et al. 2013

Journal of the American Society of Nephrology

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“…Breeding pairs to develop Tg26 colonies were kindly gifted by Prof. Paul E. Klotman M.D., President and CEO, Baylor College of Medicine, Houston, TX. Details of these mice have been described previously (Kumar et al, 2010, 2011, 2012; Rai et al, 2013). We are maintaining the colonies of these animals in our animal facility.…”

Section: Methodsmentioning

confidence: 99%

“…The activation of renin angiotensin system (RAS) has been demonstrated to play an important role in the development as well as progression of HIVAN (Kumar et al, 2011, 2012). Modalities which either blocked the production of Ang II or inhibited the effect of Ang II have been reported to slow down the progression of HIVAN (Bird et al, 1989; Burns et al, 1999; Kimmel et al, 2003); moreover, infusion of Ang II accelerated the progression of renal lesions in a mouse model of HIVAN (Ideura et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Rai¹,

Lederman²,

Haque³

et al. 2014

Experimental and Molecular Pathology

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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.

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“…Several of these factors are also present in patients with HIV-associated nephropathy (HIVAN) (6, 7); however, the role of epigenetic factors in the development of HIVAN has not been studied so far (8). The renin angiotensin system (RAS) has been shown to play important roles in the development and progression of HIVAN (9-13). For example, infusion of Ang II enhanced progression of HIVAN in an experimental mouse model of the disease (9).…”

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confidence: 99%

“…Conversely, blockade and inhibition of Ang II production slowed down HIVAN progression both in human and animal models (10-12). Similarly, enhanced renin production accelerated progression of renal lesions, whereas inhibition of renin attenuated progression of renal lesions in Vpr transgenic mice (an HIVAN model) (13). Recent reports indicate that lack of VDR in the genome of T cells is associated with the activation of the RAS (14).…”

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confidence: 99%

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu

Chandel

Ayasolla

Lan

et al. 2015

Journal of Molecular Biology

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HIV has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system (RAS); however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors are contributing to down regulation of VDR. Kidney cells in HIV transgenic mice as well as HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhancesexpression of histone deacetylase (HDAC) 1, DNA methyl transferase (DNMT) 3b and DNMT1. 293T cells, when stably transfected with SNAIL (SNAIL/293T), displayed suppressed transcription and translation of VDR. In SNAIL/293T cells, co-immunoprecipitation studies revealed the association of HDAC1, DNMT3b, DNMT1, and mSin3A with SNAIL. Chromatin immunoprecipitation (ChIP) experiments confirmed the presence of the SNAIL repressor complex at the VDR promoter. Consistent with the enhanced DNA methyl transferase expression in HIV/HPs, there was an increased CpG methylation at the VDR promoter. ChIP assay confirmed occurrence of H3K4 trimethylation on SNAIL promoter. Neither VDR agonist (VDA) nor an HDAC inhibitor (HDACI) nor demethylating agent (DAC) individually could optimally upregulate VDR in HIV milieu. However, VDA and HDACI when combined were successful in de-repressing VDR expression. Our findings demonstrate that SNAIL recruits multiple chromatin enzymes to form a repressor complex in HIV milieu which down regulates VDR expression.

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Inhibition of renin activity slows down the progression of HIV-associated nephropathy

Cited by 11 publications

References 39 publications

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu

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