The renin- Angiotensin- Aldosterone System (RAAS) has been demonstrated to play an important role in the development and progression of renal lesions in both human and animal models of focal glomerulosclerosis (FGS). Interestingly, pharmaceutical agents which modulate the effects of Ang II have been the only ones investigated and proven to alter the course of HIV-associated nephropathy (HIVAN). Since inhibition of two other components of RAAS- eplerenone (a selective inhibitor of aldosterone) and aliskiren (a selective renin inhibitor) have also been reported to modulate the progression of renal lesions in non-HIVAN models of FGS, we hypothesize that use of these agents either alone or in combination with ACE (angiotensin I converting enzyme) inhibitors/AT1 receptor blockers will not only attenuate or prevent HIV-1-induced injury but also delay or slow down the progression of HIVAN. In preliminary studies, we observed that renal cells in mice transgenic HIV-1 genes (HIVAN mice, Tg26) not only showed activation of the mTOR pathway but also displayed enhanced epithelial mesenchymal transdifferentiation (EMT). Interestingly, aliskiren not only inhibited the activation of mTOR pathway as well as renal cell EMT but also attenuated HIVAN phenotype. Moreover, renal tissue of HIVAN (Tg26) mice showed six-fold increase in renin mRNA expression. These findings indicate that the activation of EMT and mTOR pathways in renal cells may be mediated either directly through renin or its downstream effector molecules such as Ang II. Since the activation of the RAAS (host factor) and or African descent (genetic factor) alone has not been shown to manifest into HIVAN phenotype in other renal disease models, it appears that manifestation of HIVAN phenotype requires specific environmental factors, such as renal cell expression of HIV-1 genes. Although, we can not change the ancestry but we can modulate the environmental (HIV-1 infection) and host factors. Based on our preliminary data, we hypothesize that modulation of RAAS by its selective inhibitors will not only prevent or attenuate HIV-1- induced renal injury but also delay or slow down the progression of HIVAN.

Public Health Relevance

Patients infected with HIV-1 are prone to develop a rapidly progressing kidney disease termed HIV-associated nephropathy (HIVAN). HIVAN is the third leading cause of End-stage renal disease among individuals with African American background, and is associated with the highest rates of hospitalizations in this population. At present, there is no specific treatment to cure this disease. Since activation of Renin-Angiotensin- Aldosterone System plays an important role in the progression of renal diseases in general, we intend to evaluate the effect of its inhibition in HIVAN. Our long term research goal is to develop strategies to slow down the progression as well as find a cure of this devastating kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084910-03
Application #
8304380
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kimmel, Paul
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$323,536
Indirect Cost
$128,635
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Pan, Yangbin; Wan, Jianxin; Liu, Yipeng et al. (2014) sPLA2 IB induces human podocyte apoptosis via the M-type phospholipase A2 receptor. Sci Rep 4:6660
Plagov, Andrei; Lan, Xiqian; Rai, Partab et al. (2014) Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN. Histol Histopathol 29:1575-81
Chandel, Nirupama; Ayasolla, Kamesh; Lan, Xiqian et al. (2014) Renin modulates HIV replication in T cells. J Leukoc Biol 96:601-9
Rai, Partab; Lederman, Rivka; Haque, Shabirul et al. (2014) Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN. Exp Mol Pathol 96:431-7
Lan, Xiqian; Jhaveri, Aakash; Cheng, Kang et al. (2014) APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability. Am J Physiol Renal Physiol 307:F326-36
Rai, Partab; Plagov, Andrei; Kumar, Dileep et al. (2013) Rapamycin-induced modulation of HIV gene transcription attenuates progression of HIVAN. Exp Mol Pathol 94:255-61
Rattanavich, Rungwasee; Plagov, Andrei; Kumar, Dileep et al. (2013) Deficit of p66ShcA restores redox-sensitive stress response program in cisplatin-induced acute kidney injury. Exp Mol Pathol 94:445-52
Chandel, Nirupama; Husain, Mohammad; Goel, Hersh et al. (2013) VDR hypermethylation and HIV-induced T cell loss. J Leukoc Biol 93:623-31
Chen, Xinghua; Ren, Zhilong; Liang, Wei et al. (2013) c-Abl mediates angiotensin II-induced apoptosis in podocytes. J Mol Histol 44:597-608
Rehman, Shabina; Chandel, Nirupama; Salhan, Divya et al. (2013) Ethanol and vitamin D receptor in T cell apoptosis. J Neuroimmune Pharmacol 8:251-61

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