Abstract
Background/Aims: Obesity-related kidney disease is associated with elevated levels of saturated free fatty acids (SFA). SFA lipotoxicity in tubular cells contributes to significant cellular apoptosis and injury. Salvianolic acid B (SalB) is the most abundant bioactive molecule from Radix Salviae Miltiorrhizae. In this study, we investigated the effect of SalB on SFA-induced renal tubular injury and endoplasmic reticulum (ER) stress, in vivo and in vitro. Methods: C57BL/6 mice were assigned to five groups: a control group with normal diet (Nor), high-fat diet group (HFD), and HFD with three different SalB treatment doses, low (SalBL; 3 mg/kg), medium (SalBM; 6.25 mg/kg), and high (SalBH; 12.5 mg/kg) doses. SalB was intraperitoneally injected daily for 4 weeks after 8 weeks of HFD. After 12 weeks, mice were sacrificed and kidneys and sera were collected. Apoptosis and ER stress were induced in human proximal tubule epitelial (HK2) cells by palmitic acid (PA, 0.6 mM), tunicamycin (TM, 1 μg/ml), or thapsigargin (TG, 200 nM) in vitro. Results: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks exhibited increased apoptosis (Bax and cleaved caspase-3) and ER stress (BIP, P-eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1s) markers expression in the kidney, compared with control mice, which were remarkably suppressed by SalB treatment. In vitro studies showed that PA (0.6 mM) induced apoptosis and ER stress in cultured HK2 cells. SalB treatment attenuated all the adverse effects of PA. However, SalB failed to inhibit TM or TG-induced ER stress in HK2 cells. Conclusion: The study indicated that SalB may play an important role in obesity-related kidney injury via mediating SFA-induced ER stress.
Highlights
Obesity is one of the biggest health issues globally, in recent decades
Oil red O staining revealed that the high-fat diet (HFD) mice had increased kidney lipid accumulation in both tubules and glomeruli, which was significantly decreased by Salvianolic acid B (SalB) treatment (Figures 1B,C)
Further western blotting experiments showed that Intercellular cell adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) expressions were upregulated in the kidney cortex of the HFD mice, while suppressed by SalB treatment (Figures 1D,E)
Summary
Obesity is one of the biggest health issues globally, in recent decades. It is considered a risk factor for developing chronic kidney disease (CKD) and kidney injury, which are characterized by structural remodeling of the kidney tissue, including glomerulomegaly, tubular apoptosis, and interstitial fibrosis (Wu and Kaufman, 2006; Alicic et al, 2013; Redon and Lurbe, 2015). Lipotoxicity mediated by increased intracellular SFA and their metabolites, accompanied with persistent proteinuria, can aggravate dysfunctional tubule response and epithelial apoptosis. This is followed by an inflammatory response and fibrosis, which contribute to nephropathy progression (Weinberg, 2006; Lindenmeyer et al, 2008). Increased intrarenal fatty acid levels can reportedly trigger oxidative and ER stress, which in turn activates the unfolded protein response (UPR) and cell apoptosis (Rutkowski and Kaufman, 2004; Xu et al, 2005; Zhang and Kaufman, 2006; Ron and Walter, 2007; Cao et al, 2012). Once released from BIP upon accumulation of misfolded proteins, ATF6 traffics to the Golgi complex to mediate the adaptive response to ER protein misfolding (Han and Kaufman, 2016)
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