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Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity-induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl-CoA carboxylase (ACC) activities, as well as a histological examination. HFD induced metabolic derangement, systemic insulin resistance and glomerular mesangial matrix expansion. The administration of metformin reduced HFD-induced metabolic derangement and renal injury. The administration of metformin reduced the HFD-induced increase in adipokine expression and macrophage infiltration. Moreover, renal AMPK activity, which was decreased by HFD, was recovered following the administration of metformin; in addition, fatty acid oxidation was increased by the inhibition of ACC. These results indicate that metformin exerts beneficial effects on obesity-induced renal injury by regulating systemic inflammation, insulin resistance and the renal AMPK/ACC pathway. The clinical application of metformin to obese or early diabetic patients may be helpful in preventing obesity- or diabetes-related kidney disease.

Ischemia followed by reperfusion induces microvascular endothelial cell injury, leading to the loss of functions such as regulation of vascular tone, tissue perfusion, permeability, and inflammation in kidney. Improvement of this endothelial dysfunction could be a good approach to treating ischemia-reperfusion-induced renal injury. Cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) is a variant of native angiogenic factor angiopoietin-1 engineered to have higher activity. We evaluated the protective effect of COMP-Ang1 in an ischemia-reperfusion renal injury model. COMP-Ang1 preserved renal peritubular capillaries after ischemia-reperfusion injury without recruiting pericytes. Pretreatment with COMP-Ang1 attenuated the increase of blood urea nitrogen and serum creatinine levels after ischemia-reperfusion. In addition, the morphological examination indicated less tubular injury in mice pretreated with COMP-Ang1 than in those treated with the vehicle. COMP-Ang1 treatment reduced the increase in the number of Gr-1-positive neutrophils or ER-HR3-positive macrophages infiltrating kidneys, increased phosphorylation of Akt, and preserved renal tissue perfusion flow and microvascular permeability. Furthermore, COMP-Ang1 decreased renal interstitial fibrosis 30 days after the ischemia-reperfusion injury. In conclusion, COMP-Ang1 can be a possible endothelial cell-targeted therapy for preventing ischemia-reperfusion-induced acute kidney injury.

Background: Peritubular capillary injury induces chronic hypoxia in the renal tubulointerstitium, and renal peritubular capillary dysfunction is an early event that contributes to tubulointerstitial fibrosis. Cyclosporine A (CsA) is a potent immunosuppressant and improves survival of renal allografts. However, the limitation of CsA use is chronic nephrotoxicity. A soluble, stable and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1 has been developed. We investigated whether COMP-Ang1 ameliorates CsA-induced renal injury., Methods: CsA-treated mice were injected with recombinant adenovirus expressing either COMP-Ang1 or LacZ. Histology, inflammatory, haemodynamic and fibrotic parameters, and signalling pathway were evaluated., Results: Histologic examination showed that COMP-Ang1 significantly decreased CsA-induced tubular damage and tubulointerstitial fibrosis. CsA-induced increases in macrophage infiltration and expression of MCP-1 and ICAM-1 after CsA treatment were significantly reduced by COMP-Ang1. Treatment with COMP-Ang1 also decreased the CsA-induced increases in TGF-beta1 and Smad 2/3 levels while increasing Smad 7 levels. Laser-Doppler sonographic findings and endothelial factor VIII staining revealed that COMP-Ang1 preserved the integrity of peritubular vasculature and intrarenal haemodynamics from the CsA-induced renal injury. COMP-Ang1 inhibited tubular cell apoptosis while increasing tubular cell proliferation in CsA-induced renal injury., Conclusions: These results indicate that COMP-Ang1 exhibited a protective effect on damaged peritubular capillaries, haemodynamic alteration and inflammation in CsA-induced renal injury. Thus, COMP-Ang1 may be useful as a therapeutic and prophylactic agent for specific protection against endothelial dysfunction and inflammation.

Background: Inflammatory processes have been recently seen as underlying the pathogenesis of diabetic nephropathy. Angiopoietin-1 (Ang1) plays essential roles in regulating vascular growth, development, maturation, permeability and inflammation. We have developed a soluble, stable and potent Ang1 variant, cartilage oligomeric matrix protein (COMP)-Ang1., Methods: In this study, db/db mice were treated with recombinant adenovirus expressing either COMP-Ang1 or LacZ. Histology, inflammatory, metabolic, and fibrotic parameters and signalling pathway were evaluated., Results: COMP-Ang1 reduced albuminuria and decreased mesangial expansion, thickening of the glomerular basement membrane and podocyte foot process broadening and effacement. COMP-Ang1 suppressed both renal expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 and monocyte/macrophage infiltration in diabetic db/db mice. COMP-Ang1 also reduced renal tissue levels of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin, fibronectin, as well as Smad 2/3 expression, but increased Smad 7 expression. In human umbilical vein endothelial cells (HUVECs) grown in high glucose concentrations of glucose, recombinant COMP-Ang1 protein decreased nuclear factor-kappaB (NF-kappaB) expression. COMP-Ang1-mediated inhibition of increased NF-kappaB-DNA binding in nuclear extracts from HUVECs grown in high glucose was significantly blocked by soluble Tie2 receptor-Fc. In addition, COMP-Ang1 significantly decreased fasting blood glucose level, epididymal fat weight to body weight ratio, and epididymal adipocyte size in diabetic db/db mice. After intraperitoneal glucose challenge, COMP-Ang1 significantly lowered plasma glucose levels. However, there was no difference in serum insulin levels., Conclusion: We conclude that COMP-Ang1 delayed the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects.

Injury to the renal microvasculature may be a major factor in the progression of renal disease; therefore, protection of endothelial cells (EC) in renal vasculature may have a therapeutic role in renal fibrosis. Recently, a soluble, stable, and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, was developed. The contribution of COMP-Ang1 in renal interstitial fibrosis, however, remains to be clarified. This study investigated the effects of COMP-Ang1 on peritubular capillary EC in the renal cortex and the renal fibrogenic process that is triggered by unilateral ureteral obstruction. COMP-Ang1 preserved renal platelet-EC adhesion molecule-1-and Tie2-positive EC. Morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 than vehicle-treated mice. Interstitial type I collagen and myofibroblast accumulation were significantly suppressed by COMP-Ang1 treatment. COMP-Ang1 increased Tie2 and Akt phosphorylation in ureteral obstructed kidneys. Renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 than with vehicle. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of TGF-beta1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. These results demonstrate that COMP-Ang1 treatment can decrease the progression of renal fibrosis in unilateral ureteral obstruction. COMP-Ang1 may be an endothelium-specific therapeutic modality in fibrotic renal disease.

Background Activation of mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity protein phosphatase, regulates mitogen-activated protein kinase signaling. C-Jun N-terminal kinase (JNK) and p38 are activated in cisplatin-induced renal injury. However, the change of MKP-1 expression in cisplatin-induced renal injury and the regulatory effect of sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide–dependent deacetylase, on MKP-1 remains unknown. Methods To address these issues, we used constitutional Sirt2 knockout (KO) mice, transgenic (TG) mice with increased expression of SIRT2 specifically in proximal tubular epithelial cellsand wild-type (WT) mice. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin. Results MKP-1 expression in the kidney was decreased after cisplatin treatment. Cisplatin-induced downregulation of MKP-1 was reversed in Sirt2 KO mice kidney and further decreased in Sirt2 TG mice kidney. We observed similar phenomenon with SIRT2-knockdown or SIRT2-overexpressed tubular epithelial cells. Phosphorylation of p38 and JNK, a downstream signal pathway of MKP-1, increased in WT mice kidney following treatment with cisplatin. A decrease in SIRT2 suppressed cisplatin-induced phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Overexpression of SIRT2 further increased phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Acetylation of MKP-1 was significantly increased in SIRT2-knockdown cells and decreased in SIRT2-overexpressed cells after cisplatin stimulation. Sirt2 KO mice and Sirt2 TG mice showed amelioration and aggravation of renal injury, apoptosis, necroptosis and inflammation induced by cisplatin. Conclusion Our data show that SIRT2 is associated with cisplatin-induced renal injury through regulation of MKP-1 expression. [ABSTRACT FROM AUTHOR]

Abstract: As the increased acetylation of p65 is linked to nuclear factor-κB (NF-κB) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-κB and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-κB p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-κB during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-κB p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-κB through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage. [Copyright &y& Elsevier]