Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Rai, Partab; Lederman, Rivka; Haque, Shabirul; Rehman, Shabina; Kumar, Viki; Sataranatrajan, Kavithalakshmi; Malhotra, Ashwani; Kasinath, Balakuntalam S.; Singhal, Pravin C.

doi:10.1016/j.yexmp.2014.04.004

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…This is consistent with a recent clinical study showing that serum renin activities were similar in non-HIV and HIV-infected subjects while on ad libitum sodium diet and were similarly increased by a low sodium diet [38]. HIV enhances Ang II production and renin expression through the vitamin D receptor [39]; the role of vitamin D in the HIV-related renin response to a low sodium diet remains to be determined.…”

Section: Plos Onesupporting

confidence: 90%

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

et al. 2022

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HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.

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Section: Plos Onesupporting

confidence: 90%

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

et al. 2022

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“…Finally, another pathway that contributes to the development of HIV nephropathy is RAAS-dependent phosphorylation and activation of mTOR. Interestingly, this is blocked by AT2 but not AT1 antagonists, demonstrating the involvement of the putatively “protective” AT2 receptor in the pathogenesis of HIV nephropathy [ 50 ]. In view of all the findings above, it is not surprising that ACE inhibitors [ 51 ] and AT1 receptor blockers [ 52 ] are protective of progressive proteinuria and renal dysfunction in subjects with HIV nephropathy.…”

Section: The Renin-angiotensin Systemmentioning

confidence: 99%

Hypertension and Metabolic Syndrome in Persons with HIV

et al. 2020

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Purpose of Review With the advent of highly active antiretroviral therapy (ART), the life span of persons with HIV (PWH) has been nearly normalized. With aging, prevalence of the metabolic syndrome (MetS), including hypertension, has increased in the HIV population and exceeds that in the general population in some studies. This is due to a combination of traditional risk factors in addition to the effects attributable to the virus and ART. We review recent findings on the mechanisms contributing to MetS and hypertension in PWH, particularly those specific to the viral infection and to ART. Recent Findings Activation of the renin-angiotensin-aldosterone system (RAAS) and chronic immune activation contribute to the development of MetS and hypertension in PWH. HIV proteins and some ART agents alter adipocyte health contributing to dyslipidemias, weight gain, and insulin resistance. HIV infection also contributes to hypertension by direct effects on the RAAS that intertwine with inflammation by the RAAS also contributing to T cell activation. Summary Recent data suggest that in addition to current ART, therapeutic targeting of the MetS and hypertension in PWH, by interfering with the RAAS, treating insulin resistance directly or by use of immunomodulators that dampen inflammation, may be critical for preventing or treating these risk factors and to improve overall cardiovascular complications in the HIV-infected aging population.

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“…Thus, inactivation of mTOR is an important protective mechanism underlying the involvement of ALS in the pathological process of cardiac hypertrophy. It was previously reported that the activation of RAS stimulates the mTOR pathway in HIV-associated nephropathy (33). In addition, ALS and valsartan were found to improve metabolic signaling, oxidative stress, and myocardial tissue remodeling, at least partially, through the activation of p-mTOR expression (24).…”

Section: Discussionmentioning

confidence: 94%

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Zhao

Liu

Guo³

2020

Braz J Med Biol Res

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Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg Á kg-1 Á day-1) for 4 weeks, with or without ALS treatment at 20 mg Á kg-1 Á day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

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Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Cited by 13 publications

References 39 publications

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

Hypertension and Metabolic Syndrome in Persons with HIV

Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

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