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Yao F.,Hebei Medical University | Yao F.,Key Laboratory of Kidney Diseases of Hebei Province | Li Z.,Hebei Medical University | Li Z.,The First Hospital of Changsha City | And 12 more authors.
Molecular and Cellular Endocrinology | Year: 2015

Type 2 diabetes is characterized by hyperglycemia and deregulated lipid metabolism with increased plasma non-esterified fatty acids (NEFA). Apoptosis of glomerular cells is a hallmark in diabetic glomerulosclerosis. Fatty acid-binding protein 4 (FABP4), a carrier protein for fatty acids, has been linked to diabetes and diabetic nephropathy (DN). Here we aimed to investigate the link between FABP4 and apoptosis in diabetic glomerulosclerosis. We first evaluated the presence of FABP4 and ER stress markers as well as apoptosis-related proteins in renal biopsies of patients with DN. Then we used FABP4 inhibitor BMS309403 or siRNA to further investigate the role of FABP4 in ER stress and apoptosis induced by NEFA or high glucose in cultured human mesangial cells (HMCs).We found FABP4 was expressed mainly in glomerular mesangial cells of the human renal biopsies and the glomerular FABP4 was increased in renal biopsies of DN. The up-regulation of FABP4 was accompanied with increased glucose-regulated protein 78 (GRP78) and Caspase-12 as well as down-regulated B-cell CLL/lymphoma 2 (Bcl-2) in glomeruli. Along with the induction of FABP4 and apoptosis, GRP78 and its three sensors as well as C/EBP homologous protein (CHOP) and Caspase-12 were induced in HMCs treated with NEFA or high glucose and these responses were attenuated or even abrogated by treating with FABP4 inhibitor or FABP4 siRNA. Ultrastructure observation confirmed the lipotoxicity of oleic acid by showing the morphological damage in HMCs. Our data suggest that FABP4 in glomerular mesangial cells is up-regulated in DN and FABP4 mediates apoptosis via the ER stress in HMCs. © 2015 Elsevier Ireland Ltd.

Niu H.,Hebei Medical University | Niu H.,Key Laboratory of Kidney Diseases of Hebei Province | Nie L.,Yale University | Nie L.,VA Connecticut Healthcare System | And 8 more authors.
BMC Nephrology | Year: 2014

Background: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and is associated with excessive cardiovascular morbidity and mortality. The angiotensin converting enzyme inhibitor (ACEI) benazepril has been shown to slow the progression of chronic renal disease and have beneficial effects in patients with a combination of chronic renal disease and cardiovascular disease. Transforming growth factor-β1(TGF-β1) plays a central role in the pathogenesis and progression of DN. Integrin-linked kinase (ILK) can modulate TGF-β1-induced glomerular mesangial cell (GMC) injury, which is a prominent characteristic of renal pathology in kidney diseases. As an integrin cytoplasmic-binding protein, ILK regulates fibronectin (FN) matrix deposition and the actin cytoskeleton. Smooth muscle α-actin (α-SMA) is involved in progressive renal dysfunction in both human and experimental renal disease. Methods. To explore the mechanisms of benazepril's reno-protective effects, we examined the expression of TGF-β1, ILK, and α-SMA in GMC exposed to high glucose (HG) and in the kidneys of streptozotocin (STZ)-induced diabetic rats using real-time quantitative RT-PCR and western blot analysis. To elucidate the mechanism(s) of the effect of benazepril on GMC cellular processes, we assessed the effect of benazepril on Angiotensin II (Ang II) signalling pathways using western blot analysis. Results: The expression of TGF-β1, ILK, and α-SMA increased significantly in the diabetic group compared with the control group. Benazepril treatment inhibited the expression of these genes in DN but failed to rescue the same levels in the control group. Similar results were found in GMC treated with HG or benazepril. Ang II increased ERK and Akt phosphorylation in the HG group, and benazepril could not completely block these responses, suggesting that other molecules might be involved in the progression of DN. Our findings suggest that benazepril decreases ILK and α-SMA expression, at least in part, by affecting the interactions between Ang II and TGF-β1. Conclusions: The findings described here support the hypothesis that the HG milieu of diabetes increases TGF-β1secretion, which increases the synthesis of ILK and α-SMA that are involved in the progression of DN. This might be an important mechanism of the benazepril renal-protective function in the pathogenesis of DN. © 2014 Niu et al.; licensee BioMed Central Ltd.

Haijiang W.,Hebei Medical University | Haijiang W.,Key Laboratory of Kidney Diseases of Hebei Province | Yonghong S.,Hebei Medical University | Yonghong S.,Key Laboratory of Kidney Diseases of Hebei Province | And 14 more authors.
Molecular and Cellular Endocrinology | Year: 2015

Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. Invitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPARγ and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney. © 2015 Elsevier Ireland Ltd.

Wei J.,Hebei Medical University | Wei J.,Key Laboratory of Kidney Diseases of Hebei Province | Shi Y.,Hebei Medical University | Shi Y.,Key Laboratory of Kidney Diseases of Hebei Province | And 11 more authors.
Cellular Signalling | Year: 2013

Epithelial to mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both high glucose and transforming growth factor-β (TGF-β) are able to induce EMT in cell culture. In this study, we examined the role of the thioredoxin-interacting protein (TXNIP) on EMT induced by high glucose or TGF-β1 in HK-2 cells. EMT was assessed by the expression of α-smooth muscle actin (α-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. High glucose (30. mM) was shown to induce EMT at 72. h. This was blocked by knockdown of TXNIP or antioxidant NAC. Meanwhile, we also found that knockdown of TXNIP or antioxidant NAC inhibited high glucose-induced generation of reactive oxygen species (ROS), phosphorylation of p38 MAPK and ERK1/2 and expression of TGF-β1. HK-2 cells that were exposed to TGF-β1 (4. ng/ml) also underwent EMT. The expression of TXNIP gene and protein was increased in HK-2 cells treated with TGF-β1. Transfection with TXNIP shRNA was able to attenuate TGF-β1 induced-EMT. These results suggested that knockdown of TXNIP antagonized high glucose-induced EMT by inhibiting ROS production, activation of p38 MAPK and ERK1/2, and expression of TGF-β1, highlighting TXNIP as a potential therapy target for diabetic nephropathy. © 2013 Elsevier Inc.

Zhao J.,Hebei University | Niu H.,Hebei Medical University | Niu H.,Key Laboratory of Kidney Diseases of Hebei Province | Li A.,Hebei University | Nie L.,Hebei Medical University
PLoS ONE | Year: 2016

The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL), a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF) signaling and angiogenesis in endothelial cells (ECs). We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/ 44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day) recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis. © 2016 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Wu H.,Hebei Medical University | Wu H.,Key Laboratory of Kidney Diseases of Hebei Province | Deng X.,Hebei General Hospital | Shi Y.,Hebei Medical University | And 7 more authors.
Journal of Endocrinology | Year: 2016

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review. © 2016 Society for Endocrinology.

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