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 #
5R01DK084910-04
Application #
8527768
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
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$304,881
Indirect Cost
$121,218
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Haque, Shabirul; Lan, Xiqian; Wen, Hongxiu et al. (2016) HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy. Am J Pathol 186:347-58
Khatua, Atanu K; Cheatham, Amber M; Kruzel, Etty D et al. (2015) Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1. Am J Physiol Cell Physiol 309:C22-37
Chandel, Nirupama; Ayasolla, Kameshwar S; Lan, Xiqian et al. (2015) Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu. J Mol Biol 427:3201-15
Rai, Partab; Singh, Tejinder; Lederman, Rivka et al. (2015) Hyperglycemia enhances kidney cell injury in HIVAN through down-regulation of vitamin D receptors. Cell Signal 27:460-9
Lan, Xiqian; Wen, Hongxiu; Saleem, Moin A et al. (2015) Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu. Exp Mol Pathol 98:491-501
Liu, Yipeng; Liang, Wei; Yang, Yingjie et al. (2015) IQGAP1 regulates actin cytoskeleton organization in podocytes through interaction with nephrin. Cell Signal 27:867-77
Singh, Tejinder; Ayasolla, Kamesh; Rai, Partab et al. (2015) AT1R blockade in adverse milieus: role of SMRT and corepressor complexes. Am J Physiol Renal Physiol 309:F189-203
Ayasolla, Kamesh R; Rai, Partab; Rahimipour, Shai et al. (2015) Tubular cell phenotype in HIV-associated nephropathy: role of phospholipid lysophosphatidic acid. Exp Mol Pathol 99:109-15
Lan, Xiqian; Wen, Hongxiu; Lederman, Rivka et al. (2015) Protein domains of APOL1 and its risk variants. Exp Mol Pathol 99:139-44
Chandel, Nirupama; Ayasolla, Kamesh; Lan, Xiqian et al. (2014) Renin modulates HIV replication in T cells. J Leukoc Biol 96:601-9

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