Fabrication of all-trans retinoic acid loaded chitosan/tripolyphosphate lipid hybrid nanoparticles as a novel oral delivery approach for management of diabetic nephropathy in rats

Diabetic nephropathy (DN) involves damage associated to hyperglycemia and oxidative stress. Renal fibrosis is a major pathologic feature of DN. The aim of this study was to evaluate anti-fibrogenic and renoprotective effects of all-trans retinoic acid (ATRA) in isolated glomeruli and proximal tubules of diabetic rats. Diabetes was induced by single injection of streptozotocin (STZ, 60 mg/Kg). ATRA (1 mg/Kg) was administered daily by gavage, from days 3–21 after STZ injection. ATRA attenuated kidney injury through the reduction of proteinuria, renal hypertrophy, increase in natriuresis, as well as early markers of damage such as β2-microglobulin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). The following parameters increased: macrophage infiltration, localization of alpha-smooth muscle actin (αSMA)-positive cells in renal tissue, and pro-fibrotic proteins such as transforming growth factor-β (TGF-β1), laminin beta 1 (LAM-β1), and collagens IV and I. Remarkably, ATRA treatment ameliorated these alterations and attenuated expression and nuclear translocation of Smad3, with increment of glomerular and tubular Smad7. The diabetic condition decreased expression of retinoic acid receptor alpha (RAR-α) through phosphorylation in serine residues mediated by the activation of c-Jun N-terminal kinase (JNK). ATRA administration restored the expression of RAR-α and inhibited direct interactions of JNK/RAR-α. ATRA prevented fibrogenesis through down-regulation of TGF-β1/Smad3 signaling.

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All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF-κB during initiation of diabetic nephropathy

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2018.06.002 ◽

2018 ◽

Vol 60 ◽

pp. 47-60 ◽

Cited By ~ 14

Author(s):

Edith Sierra-Mondragon ◽

Eduardo Molina-Jijon ◽

Carmen Namorado-Tonix ◽

Rafael Rodríguez-Muñoz ◽

Jose Pedraza-Chaverri ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Retinoic Acid ◽

Inflammatory Response ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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All-trans retinoic acid suppresses bone morphogenetic protein 4 in mouse diabetic nephropathy through a unique retinoic acid response element

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00218.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E418-E431 ◽

Cited By ~ 3

Author(s):

Masanori Tamaki ◽

Tatsuya Tominaga ◽

Yui Fujita ◽

Yasuhiko Koezuka ◽

Go Ichien ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Retinoic Acid ◽

Regulatory Mechanism ◽

Bone Morphogenetic Protein 4 ◽

Diabetic Mice ◽

Mesangial Matrix ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Morphogenetic Protein ◽

Matrix Expansion

Diabetic nephropathy (DN) causes mesangial matrix expansion, which results in glomerulosclerosis and renal failure. Collagen IV (COL4) is a major component of the mesangial matrix that is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Because previous studies showed that retinoids treatment had a beneficial effect on kidney disease, we investigated the therapeutic potential of retinoids in DN, focusing especially on the regulatory mechanism of BMP4. Diabetes was induced with streptozotocin in 12-wk-old male Crl:CD1(ICR) mice, and, 1 mo later, we initiated intraperitoneal injection of all-trans retinoic acid (ATRA) three times weekly. Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 wk of age. ATRA administration alleviated DN and downregulated BMP4, phosopho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor-α (RARα) agonist significantly decreased BMP4 and COL4 expression. Genomic analysis suggested two putative retinoic acid response elements (RAREs) for the mouse Bmp4 gene. Chromatin immunoprecipitation analysis and reporter assays indicated a putative RARE of the Bmp4 gene, located 11,488–11,501 bp upstream of exon 1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition. ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.

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Tripterine and all-trans retinoic acid (ATRA) – loaded lipid-polymer hybrid nanoparticles for synergistic anti-arthritic therapy against inflammatory arthritis

Artificial Cells Nanomedicine and Biotechnology ◽

10.1080/21691401.2021.1964983 ◽

2021 ◽

Vol 49 (1) ◽

pp. 576-586

Author(s):

Jichao Li ◽

Zeng Zhang ◽

Xiaohan Huang

Keyword(s):

Retinoic Acid ◽

Inflammatory Arthritis ◽

Hybrid Nanoparticles ◽

Polymer Hybrid ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Oral Delivery of Particulate Transforming Growth Factor Beta 1 and All-Trans Retinoic Acid Reduces Gut Inflammation in Murine Models of Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjv089 ◽

2015 ◽

Vol 9 (8) ◽

pp. 647-658 ◽

Cited By ~ 14

Author(s):

Thomas F. Conway ◽

Laura Hammer ◽

Stacia Furtado ◽

Edith Mathiowitz ◽

Ferdinando Nicoletti ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Retinoic Acid ◽

Transforming Growth Factor Beta ◽

Oral Delivery ◽

Transforming Growth Factor ◽

Murine Models ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Inflammatory Bowel ◽

Growth Factor Beta

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Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab204 ◽

2021 ◽

Author(s):

Ferdinando Nicoletti ◽

Laura Hammer ◽

Stacia Furtado ◽

Katia Mangano ◽

Edith Mathiowitz ◽

...

Keyword(s):

Retinoic Acid ◽

Side Effects ◽

Oral Delivery ◽

Transforming Growth Factor ◽

Systemic Exposure ◽

Biologically Active ◽

Rodent Models ◽

Murine Models ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Background All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA’s key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-β and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. Methods We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. Results In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. Conclusions We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.

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