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Role of the retinoic acid receptor-? in HIV-associated nephropathy.

ABSTRACT: All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-? (RAR?). Here, we report that Am580, a water-soluble RAR?-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RAR?-/- Tg26 mice developed more severe kidney and podocyte injury than did RAR?+/- Tg26 mice. Am580 failed to ameliorate kidney injury in RAR?-/- Tg26 mice, confirming our hypothesis that Am580 acts through RAR?. Although the expression of RAR?-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RAR? in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RAR? agonists may be potential agents for the treatment of HIVAN.

SUBMITTER: Ratnam KK

PROVIDER: S-EPMC3050085 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Role of the retinoic acid receptor-α in HIV-associated nephropathy.

Ratnam Krishna K KK Feng Xiaobei X Chuang Peter Y PY Verma Vikram V Lu Ting-Chi TC Wang Jinshan J Jin Yuanmeng Y Farias Eduardo F EF Napoli Joseph L JL Chen Nan N Kaufman Lewis L Takano Tomoko T D'Agati Vivette D VD Klotman Paul E PE He John C JC

Kidney international 20101208 6

All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Fur ...[more]

PMID: 21150871

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Project description:BackgroundHuman immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of end stage kidney disease (ESKD) in human immunodeficiency virus-1 (HIV-1) serotype patients and it mostly affects patients of African descent. It rapidly progresses to ESKD if untreated. The goal of treatment is directed toward reducing HIV-1 replication and/or slowing the progression of chronic kidney disease. The following pharmacological agents have been used for the treatment of HIVAN: antiretroviral therapy, angiotensin-converting enzyme inhibitors (ACEi), steroids and recently cyclosporin. Despite this, the effect of each intervention is yet to be evaluated.ObjectivesTo evaluate the benefits and harms of adjunctive therapies in the management of HIVAN and its effects on symptom severity and all-cause mortality.Search methodsIn January 2012 we searched the Cochrane Renal Group's Specialised Register, AIDS Education Global Information System (AEGIS database), ClinicalTrial.gov, the WHO International Clinical Trials Registry Portal, and reference lists of retrieved articles without language restrictions. In our original review we searched CENTRAL, MEDLINE, EMBASE, and AIDSearch, in addition to contacting individual researchers, research organisations and pharmaceutical companies.Selection criteriaRandomised controlled trials (RCTs) and quasi-RCTs of any therapy used in the treatment of HIVAN.Data collection and analysisWe independently screened the search outputs for relevant studies and to retrieve full articles when necessary. For dichotomous outcomes results were to be expressed as risk ratios with 95% confidence intervals, and for continuous scales of measurement the mean difference was to be used.Main resultsWe identified four relevant ongoing studies: one is still ongoing; two have completed recruitment but are yet to be published; and the fourth study was suspended for unspecified reasons. No completed RCTs or quasi-RCTs were identified. We summarised and tabulated the data from the observational studies, however no formal analyses were performed.Authors' conclusionsThere is currently no RCT-based evidence upon which to base guidelines for the treatment of HIVAN, however three ongoing studies have been identified. Data from observational studies suggest steroids and angiotensin-converting enzyme inhibitors appear to improve kidney function in patients with HIVAN, however no formal analyses were performed in this review. This review highlights the need for good quality RCTs to address the effects of interventions for treating this group.

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Role of the retinoic acid receptor-? in HIV-associated nephropathy.

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Role of the retinoic acid receptor-α in HIV-associated nephropathy.

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