Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.

Melatonin, a pineal hormone, is well known to regulate the sleep–wake cycle. Besides, the hormone has been shown to display pleiotropic effects arising from its powerful anti-oxidant and anti-inflammatory activities. Recent studies have reported that melatonin exerts protective effects in animal models of kidney disease. However, the potential effects of melatonin on aristolochic acid (AA)-induced nephropathy (AAN) have not yet been investigated. Here, we found that the administration of melatonin ameliorated AA-induced renal dysfunction, as evidenced by decreased plasma levels of blood urea nitrogen and creatinine and histopathological abnormalities such as tubular dilatation and cast formation. The upregulation of tubular injury markers after AA injection was reversed by melatonin. Melatonin also suppressed AA-induced oxidative stress, as evidenced by the downregulation of 4-hydroxynonenal and reduced level of malondialdehyde, and modulated expression of pro-oxidant and antioxidant enzymes. In addition, p53-dependent apoptosis of tubular epithelial cells, infiltration of macrophages and CD4⁺ T cells into damaged kidneys, and renal expression of cytokines and chemokines were inhibited by melatonin. Moreover, melatonin attenuated AA-induced tubulointerstitial fibrosis through suppression of the tumor growth factor-β/Smad signaling pathway. These results suggest that melatonin might be a potential therapeutic agent for AAN.

Accumulating evidence suggests that the pineal hormone melatonin displays protective effects against renal fibrosis, but the mechanisms remain poorly understood. Here, we investigate the effect of the pineal hormone on transdifferentiation of renal fibroblasts to myofibroblasts invoked by transforming growth factor-β1 (TGF-β1). Increased proliferation and activation of renal interstitial fibroblasts after TGF-β1 treatment were attenuated by melatonin pretreatment. Mechanistically, melatonin suppressed Smad2/3 phosphorylation and nuclear co-localization of their phosphorylated forms and Smad4 after TGF-β1 stimulation. In addition, increased phosphorylations of Akt, extracellular signal-regulated kinase 1/2, and p38 after TGF-β1 treatment were also suppressed by the hormone. These effects of melatonin were not affected by pharmacological and genetic inhibition of its membrane receptors. Furthermore, melatonin significantly reversed an increase of intracellular reactive oxygen species (ROS) and malondialdehyde levels, and a decrease of the reduced glutathione/oxidized glutathione ratio after TGF-β1 treatment. Finally, TGF-β1-induced proliferation and activation were also suppressed by N-acetylcysteine. Altogether, these findings suggest that the pineal hormone melatonin prevents TGF-β1-induced transdifferentiation of renal interstitial fibroblasts to myofibroblasts via inhibition of Smad and non-Smad signaling cadcades by inhibiting ROS-mediated mechanisms in its receptor-independent manner.

Jeon EJ, et al. J Korean Med Sci. 2016 Mar;31(3):397-402. http://dx.doi.org/10.3346/jkms.2016.31.3.397

Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

Jeon EJ. Yeungnam Univ J Med. 2018 Jun;35(1):27-35. https://doi.org/10.12701/yujm.2018.35.1.27