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.
Highlights
Diabetic nephropathy (DN) is considered a long-term diabetes mellitus complication with proteinuria, a progressive decline in renal function accompanied by glomerular and interstitial fibrosis
We studied the association between retinoic acid receptor (RAR) signaling and c-jun N-terminal kinase (JNK) pathway because they have been described as contributing to hyperglycemia-induced renal fibrogenesis
Kidney fibrosis is a common endpoint of various progressive kidney diseases such as DN, which leads to loss of nephrons and is characterized by the activation of fibroblasts, epithelial-to-mesenchymal transition, macrophage infiltration, and excessive extracellular matrix (ECM) accumulation that may lead to the development of end-stage renal disease (ESRD) [5,6]
Summary
Diabetic nephropathy (DN) is considered a long-term diabetes mellitus complication with proteinuria, a progressive decline in renal function accompanied by glomerular and interstitial fibrosis. Activation of transforming growth factor-1 (TGF-β1) signaling pathway has been demonstrated to play a detrimental role in the pathogenesis of progressive renal fibrosis [6]. Active TGF-β1 associates with its cell membrane type I and type II serine/threonine kinase receptors (TβRI and TβRII) with downstream phosphorylation in Smad 3 and Smad 2 Phosphorylated Smad forms a complex with Smad that translocates into the nucleus to regulate the expression of numerous genes that promote fibrosis [6,7,8]. Smad is an inhibitor of Smad proteins that blocks the phosphorylation of Smad and Smad, promoting its degradation [6,9,10]. Therapeutic approaches based on inhibiting TGF-β/Smad signaling have been reported to reduce renal injury and fibrosis in several pathological models, whereas overexpressing
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