Guangdong Provincial Institute of Nephrology
Guangdong Provincial Institute of Nephrology
Bai X.,State Key Laboratory of Organ Failure Research |
Bai X.,Guangdong Provincial Institute of Nephrology |
Bai X.,Southern Medical University |
Li X.,Southern Medical University |
And 6 more authors.
PLoS ONE | Year: 2014
In view of increased vascular endothelial growth factor-A (VEGF-A) expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA) and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM). In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin-induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser473-AKT, phosphorylated Thr308-AKT, nephrin, angiotensin II (Ang II), angiotensin type II receptor 1 (ATR1) were examined using quantitative real-time reverse transcription-polymerase chain reaction (RTPCR), Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr308-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr308-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr 308-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr 308-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr308-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the interstitial fibrosis, urine albumin excretion rate (UAER) and albumin to creatinine ratio. We conclude that phosphorylated Thr308-AKT regulates VEGF-A expression by interacting with either nephrin in glomeruli or Ang II in renal tubules. Antiangiogenic treatment improves renal injury and function in early experimental diabetes. © 2014 Bai et al.
Zhou Q.,Southern Medical University |
Zhou Q.,Guangdong Provincial Institute of Nephrology |
Zhou Q.,Key Laboratory for Organ Failure Research |
Zhao C.,Southern Medical University |
And 17 more authors.
BMC Nephrology | Year: 2012
Background: Acute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established. Methods: We studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine. Results: A total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI. Conclusions: Patients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease. © 2012 Zhou et al.; licensee BioMed Central Ltd.
Cao W.,Southern Medical University |
Cao W.,Guangdong Provincial Institute of Nephrology |
Cao W.,Key Laboratory for Organ Failure Research |
Zhou Q.G.,Southern Medical University |
And 17 more authors.
Journal of Hypertension | Year: 2011
Objective: Inappropriate activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension and renal injury. However, the underlying mechanisms remain elusive. Proteinuria has been shown to elicit the renal activation of RAS. The present study was performed to test the intracellular signal pathway involved in albumin-triggered activation of RAS. DESIGN AND Methods: NRK52E cells, a rat renal proximal tubular cell line, were incubated with increased levels of albumin. The rat model of protein overload was established in female Wistar-Kyoto rats that were subjected to unilateral nephrectomy followed by daily intraperitoneal injection of BSA at various doses (0.5, 1.0, and 5.0 g/kg) or combination with intragastric administration of apocynin (100 mg/kg per day), an inhibitor of NADPH oxidase. Results: Exposure of the cells to high levels of albumin activated the RAS through the endocytic receptors megalin and cubilin. High levels of albumin triggered the production of intracellular reactive oxygen species by a protein kinase C (PKC)-NADPH oxidase-dependent pathway and this, in turn, led to activation of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1). Inhibition of PKC or NADPH oxidase abolished albumin-induced activation of RAS. In a protein overload rat model, activation of RAS in renal proximal tubular cells was significantly increased, coincident with activation of PKC, NADPH oxidase, NF-κB, and AP-1. Chronic inhibition of NADPH oxidase by apocynin largely ameliorated intrarenal activation of RAS. Conclusion: Exposure of renal tubular epithelial cells with high levels of albumin triggers activation of RAS via a PKC-NADPH oxidase-dependent pathway. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Tan R.J.,University of Pittsburgh |
Zhou D.,University of Pittsburgh |
Zhou L.,Guangdong Provincial Institute of Nephrology |
Liu Y.,University of Pittsburgh
Kidney International Supplements | Year: 2014
Wnt/β-catenin signaling is an evolutionarily conserved, highly complex, key developmental pathway that regulates cell fate, organ development, tissue homeostasis, as well as injury and repair. Although relatively silent in normal adult kidney, Wnt/β-catenin signaling is re-activated after renal injury in a wide variety of animal models and in human kidney disorders. Whereas some data point to a protective role of this signaling in healing and repair after acute kidney injury, increasing evidence suggests that sustained activation of Wnt/β-catenin is associated with the development and progression of renal fibrotic lesions. In kidney cells, Wnt/β-catenin promotes the expression of numerous fibrosis-related genes such as Snail1, plasminogen activator inhibitor-1, and matrix metalloproteinase-7. Recent studies also indicate that multiple components of the renin-angiotensin system are the direct downstream targets of Wnt/β-catenin. Consistently, inhibition of Wnt/β-catenin signaling by an assortment of strategies ameliorates kidney injury and mitigates renal fibrotic lesions in various models of chronic kidney disease, suggesting that targeting this signaling could be a plausible strategy for therapeutic intervention. In this mini review, we will briefly discuss the regulation, downstream targets, and mechanisms of Wnt/β-catenin signaling in the pathogenesis of kidney fibrosis. © 2014 International Society of Nephrology.