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CTGF Inhibits BMP-7 Signaling in Diabetic Nephropathy

机译:CTGF抑制糖尿病肾病的BMP-7信号传导

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摘要

In diabetic nephropathy, connective tissue growth factor (CTGF) is upregulated and bone morphogenetic protein 7 (BMP-7) is downregulated. CTGF is known to inhibit BMP-4, but similar cross-talk between BMP-7 and CTGF has not been studied. In this study, it was hypothesized that CTGF acts as an inhibitor of BMP-7 signaling activity in diabetic nephropathy. Compared with diabetic wild-type CTGF+/+ mice, diabetic CTGF+/− mice had approximately 50% lower CTGF mRNA and protein, less severe albuminuria, no thickening of the glomerular basement membrane, and preserved matrix metalloproteinase (MMP) activity. Although the amount of BMP-7 mRNA was similar in the kidneys of diabetic CTGF+/+ and CTGF+/− mice, phosphorylation of the BMP signal transduction protein Smad1/5 and expression of the BMP target gene Id1 were lower in diabetic CTGF+/+ mice. Moreover, renal Id1 mRNA expression correlated with albuminuria (R = −0.86) and MMP activity (R = 0.76). In normoglycemic mice, intraperitoneal injection of CTGF led to a decrease of pSmad1/5 in the renal cortex. In cultured renal glomerular and tubulointerstitial cells, CTGF diminished BMP-7 signaling activity, evidenced by lower levels of pSmad1/5, Id1 mRNA, and BMP-responsive element–luciferase activity. Co-immunoprecipitation, solid-phase binding assay, and surface plasmon resonance analysis showed that CTGF binds BMP-7 with high affinity (Kd approximately 14 nM). In conclusion, upregulation of CTGF inhibits BMP-7 signal transduction in the diabetic kidney and contributes to altered gene transcription, reduced MMP activity, glomerular basement membrane thickening, and albuminuria, all of which are hallmarks of diabetic nephropathy.
机译:在糖尿病性肾病中,结缔组织生长因子(CTGF)被上调,而骨形态发生蛋白7(BMP-7)被下调。已知CTGF抑制BMP-4,但尚未研究BMP-7与CTGF之间的类似串扰。在该研究中,假设CTGF在糖尿病性肾病中充当BMP-7信号传导活性的抑制剂。与糖尿病野生型CTGF + / +小鼠相比,糖尿病CTGF +/-小鼠的CTGF mRNA和蛋白质降低约50%,严重蛋白尿少,肾小球基底膜无增厚,并且基质金属蛋白酶(MMP)活性得以保留。尽管在糖尿病CTGF + / +和CTGF +/-小鼠的肾脏中BMP-7 mRNA的含量相似,但在糖尿病CTGF + / +小鼠中BMP信号转导蛋白Smad1 / 5的磷酸化和BMP目标基因Id1的表达较低。 。此外,肾Id1 mRNA表达与蛋白尿(R = -0.86)和MMP活性(R = 0.76)相关。在血糖正常的小鼠中,腹膜内注射CTGF导致肾皮质pSmad1 / 5减少。在培养的肾小球和肾小管间质细胞中,CTGF减弱了BMP-7信号传导活性,这可通过pSmad1 / 5,Id1 mRNA和BMP响应元件荧光素酶活性的降低来证明。免疫共沉淀,固相结合测定和表面等离子体共振分析表明,CTGF以高亲和力(Kd约为14 nM)结合BMP-7。总之,CTGF的上调抑制了糖尿病肾脏中的BMP-7信号转导,并导致基因转录改变,MMP活性降低,肾小球基底膜增厚和蛋白尿,所有这些都是糖尿病性肾病的标志。

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