Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

Jin, Jing; Peng, Chao; Wu, Suzhen; Chen, Hongmin; Zhang, Baifang

doi:10.1038/aps.2015.23

Cited by 17 publications

(7 citation statements)

References 44 publications

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“…Interestingly, VEGFC also protected from a diabetes-induced increase in VEGF receptor expression in glomeruli. These data support previous observed increases in VEGFR2 expression in DN (57,58), although changes in glomerular VEGFR3 expression are not well documented. VEGFR2 and VEGFR3 expression were both reduced in D-podVEGFC mice; therefore, the potential for heterodimerization remains the same.…”

Section: Discussionsupporting

confidence: 87%

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

et al. 2018

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Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

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Section: Discussionsupporting

confidence: 87%

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

et al. 2018

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“…Histological staining Periodic acid-Schiff (PAS) and hematoxylin and eosin (H&E) staining were performed as previously described [10,11] . Briefly, the intestine samples used for histological analysis were fixed with 4% phosphate buffered paraformaldehyde for 24 h and embedded in paraffin.…”

Section: Immunohistochemical Staining For Metrnlmentioning

confidence: 99%

Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides

Fan

Zhang

et al. 2016

Acta Pharmacol Sin

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Aim: Metrnl is a novel secreted protein, but its physiological roles remain elusive. In this study, we investigated the tissue expression pattern of Metrnl in humans and explored its possible physiological role in the tissues with most highly expressed levels. Methods: A human tissue microarray containing 19 types of tissues from 69 donors was used to examine the tissue expression pattern of Metrnl, and the expression pattern was further verified in fresh human and mouse tissues. Intestinal epithelial cell-specific Metrnl knockout mice were generated, which were used to analyze the physiological roles of Metrnl. Results: Metrnl was the most highly expressed in the human gastrointestinal tract, and was specifically expressed in the intestinal epithelium. Consistent with this, Metrnl mRNA was also most highly expressed in the mouse gastrointestinal tract among the 14 types of tissues tested. In the intestinal epithelial cell-specific Metrnl knockout mice, the Metrnl levels in the gut fluid were significantly reduced, whereas the Metrnl serum levels showed a trend towards a reduction, but this change was not statistically significant. This cell-specific deletion of Metrnl did not affect body weight, food intake, blood glucose, colon length and histology, intestinal permeability, mucus content or mucin 2 expression under physiological conditions, but statistically decreased the expression of antimicrobial peptides, such as regenerating islet-derived 3 gamma (Reg3g) and lactotransferrin. Conclusion: Metrnl is highly expressed in the intestinal epithelial cells of humans and mice, which mainly contributes to the local gut Metrnl levels and affects the serum Metrnl level to a lesser extent. Metrnl plays a role in maintaining gut antimicrobial peptides.

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“…Since the progression of ESRD is irreversible, it is necessary to explore the pathogenesis of DN to identify effective methods of prevention and control. However, there are no effective therapies for patients with DN [4,5].…”

Section: Introductionmentioning

confidence: 99%

Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin

Zheng

Nie²,

Feng

et al. 2020

BMC Nephrol

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Background: Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, and is the most important cause of death for diabetic patients. Baicalin (BAI) has anti-oxidative, anti-inflammatory and antiapoptotic activities, which play a role in attenuating insulin resistance and protecting the kidney. Moreover, cellspecific targeting of renal tubular cells is an approach to enhance drug accumulation in the kidney. Methods: Forty-five Sprague-Dawley rats were divided into four groups. A diabetes model was created using streptozotocin (STZ) intraperitoneally injection. The four groups included: Control group (n = 10), DN (n = 15), BAI treatment (BAI; n = 10) and BAI-LZM treatment (BAI-LZM; n = 10) groups. In the current study, the renoprotection and anti-fibrotic effects of BAI-lysozyme (LZM) conjugate were further investigated in rats with DN induced by STZ compared with BAI treatment alone. Results: The results suggest that BAI-LZM better ameliorates renal impairment, metabolic disorder and renal fibrosis than BAI alone in rats with DN, and the potential regulatory mechanism likely involves inhibiting inflammation via the nuclear factor-κB signaling pathway, inhibiting extracellular matrix accumulation via the transforming growth factor-β/Smad3 pathway and regulating cell proliferation via the insulin-like growth factor (IGF)-1/IGF-1 receptor/ p38 Mitogen-activated protein kinase (MAPK) pathway. BAI and the kidney-targeted BAI-LZM can utilize the body's cytoprotective pathways to reactivate autophagy (as indicated by the autophagy markers mechanistic target of rapamycin and sirtuin 1 to ameliorate DN outcomes. Conclusions: Our data support the traditional use of S. baicalensis as an important anti-DN traditional chinese medicine (TCM), and BAI, above all BAI-LZM, is a promising source for the identification of molecules with anti-DN effects.

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Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

Cited by 17 publications

References 44 publications

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides

Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin

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