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Reduced Kruppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy.

ABSTRACT: Krüppel-like factor 2 (KLF2), a shear stress-inducible transcription factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular Klf2 expression was reduced in comparison with nondiabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than that of nondiabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothelial cells. To determine the role of KLF2 in streptozotocin-induced diabetic nephropathy, we used endothelial cell-specific Klf2 heterozygous knockout mice and found that diabetic knockout mice developed more kidney/glomerular hypertrophy and proteinuria than diabetic wild-type mice. Glomerular expression of Vegfa, Flk1, and angiopoietin 2 increased, but expression of Flt1, Tie2, and angiopoietin 1 decreased, in diabetic knockout mice compared with diabetic wild-type mice. Glomerular expression of ZO-1, glycocalyx, and eNOS was also decreased in diabetic knockout compared with diabetic wild-type mice. These data suggest knockdown of Klf2 expression in the endothelial cells induced more endothelial cell injury. Interestingly, podocyte injury was also more prominent in diabetic knockout compared with diabetic wild-type mice, indicating a cross talk between these two cell types. Thus, KLF2 may play a role in glomerular endothelial cell injury in early diabetic nephropathy.

SUBMITTER: Zhong F

PROVIDER: S-EPMC4312548 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Reduced Krüppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy.

Zhong Fang F Chen Habing H Wei Chengguo C Zhang Weijia W Li Zhengzhe Z Jain Mukesh K MK Chuang Peter Y PY Chen Hongyu H Wang Yongjun Y Mallipattu Sandeep K SK He John C JC

Kidney international 20140903 2

Krüppel-like factor 2 (KLF2), a shear stress-inducible transcription factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular Klf2 expression was reduced in comparison with nondiabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than that of nondiabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothel ...[more]

PMID: 25185079

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Project description:BACKGROUND:Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS:We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS:Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS:These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

Project description:UnlabelledKruppel-like factor 6 (KLF6), a zinc finger transcription factor and tumor suppressor, is induced as an immediate-early gene during hepatic stellate cell (HSC) activation. The paradoxical induction of a tumor suppressor in HSCs during proliferation led us to explore the biology of wildtype KLF6 (KLF6(WT) ) and its antagonistic, alternatively spliced isoform KLF6(SV1) in cultured HSCs and animal models. The animal models generated include a global heterozygous KLF6 mouse (Klf6+/-), and transgenic mice expressing either hKLF6(WT) or hKLF6(SV1) under the control of the Collagen α2 (I) promoter to drive HSC-specific gene expression following injury. The rat Klf6 transcript has multiple splice forms that are homologous to those of the human KLF6 gene. Following a transient increase, all rat Klf6 isoforms decreased in response to acute carbon tetrachloride (CCl(4)) liver injury and culture-induced activation. After acute CCl(4), Klf6+/- mice developed significantly increased fibrosis and enhanced fibrogenic messenger RNA (mRNA) and protein expression. In contrast, HSC-specific transgenic mice overexpressing KLF6(WT) or KLF6(SV1) developed significantly diminished fibrosis with reduced expression of fibrogenic genes. Chromatin IP and quantitative reverse-transcription polymerase chain reaction in mouse HSCs overexpressing KLF6(WT) demonstrated KLF6(WT) binding to GC boxes in promoters of Colα1 (I), Colα2 (I), and beta-platelet-derived growth factor receptor (β-Pdgfr) with reduced gene expression, consistent with transcriptional repression by KLF6. Stellate cells overexpressing either KLF6(WT) or KLF6(SV1) were more susceptible to apoptotic stress based on poly (ADP-ribose) polymerase (PARP) cleavage.ConclusionKLF6 reduces fibrogenic activity of HSCs by way of two distinct mechanisms, direct transcriptional repression of target fibrogenic genes and increased apoptosis of activated HSCs. These results suggest that following its initial induction, sustained down-regulation of KLF6 in liver injury may allow de-repression of fibrogenic genes and decreased stellate cell clearance by inhibiting apoptosis.

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Reduced Kruppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy.

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Reduced Krüppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy.

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