All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

Abstract

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.

Adipose Mesenchymal Cells-Derived EVs Alleviate DOCA-Salt-Induced Hypertension by Promoting Cardio-Renal Protection

“…All of these molecular modifications were reversed by ASC-EV administration. Renal damage and TGF-β upregulation are also associated in diseases, such as diabetes 27 …”

All-trans retinoic acid regulating angiopoietins-1 and alleviating extracellular matrix accumulation in interstitial fibrosis rats

“…ATRA is reported to be an anti-fibrosis agent in many diseases. In past decades, studies indicated that the ATRA can alleviate the fibrosis in pulmonary fibrosis [ 25 ], diabetic nephropathy [ 1 , 26 ], etc. In our studies, we found that ATRA can reduce the RIF index and down-regulate the protein expressions of Col-IV, FN and TGF-β1.…”

TGF-β1 Signaling: Immune Dynamics of Chronic Kidney Diseases

“…During inflammation, TGF-β1 facilitates the accumulation of neutrophils ( 119 , 120 ), therefore inhibiting TGF-β1 effectively alleviates neutrophil infiltration and inflammation ( 121 ). Furthermore, TGF-β1 signaling can be blocked by preventing Smad3 activation, which has been proposed as a potential therapeutic strategy for fibrotic diseases driven by neutrophil-mediated inflammation ( 122 , 123 ).…”