Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension.
Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension.
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鉴定血小板衍生生长因子 C 作为肾纤维化和高血压的介质
DOI：
10.1016/j.kint.2018.11.031
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发表时间：
2019
影响因子：
19.6
通讯作者：
Ostendorf T
中科院分区：
文献类型：
--
作者：
van Roeyen CRC;Martin IV;Drescher A;Schuett KA;Hermert D;Raffetseder U;Otten S;Buhl EM;Braun GS;Kuppe C;Liehn E;Boor P;Weiskirchen R;Eriksson U;Gross O;Eitner F;Floege J;Ostendorf T
血小板衍生生长因子（PDGF）与肾脏疾病进展有关。我们先前发现，PDGF-C在肾纤维化部位上调，并且PDGF-C的拮抗作用减少了单侧输尿管梗阻模型中的纤维化。我们研究了PDGF-C在胶原蛋白4A 3 −/−（“Alport”）小鼠中的作用，这是一种与人类肾脏疾病相关性更大的进行性肾纤维化模型。Alport小鼠与PDGF-C−/−小鼠杂交或给予PDGF-C中和抗体。PDGF-C缺乏和中和均可降低血清肌酐和血尿素氮水平，减轻肾小球损伤、肾纤维化和肾脏炎症。出乎意料的是，用中和PDGF-C抗体治疗的Alport和野生型小鼠的收缩压也降低了。PDGF-C的中和降低了Alport小鼠肾皮质的动脉壁厚度。在体外实验中，PDGF-C上调主动脉组织和原代肝细胞中的血管紧张素原，并诱导核因子κB（NFκB）/p65与肝细胞中的血管紧张素原启动子结合。PDGF-C的中和作用抑制Alport小鼠血管紧张素原的转录表达以及Alport和野生型小鼠血管紧张素II受体1型的转录表达。最后，在健康小鼠中，给予PDGF-C中和抗体可改善血管紧张素II诱导的高血压。因此，除了其在介导肾纤维化中的关键作用外，我们还通过对肾血管系统和对肾素-血管紧张素系统的影响将PDGF-C鉴定为高血压的介质。对肾纤维化和高血压的贡献使PDGF-C成为进行性肾脏疾病的有吸引力的靶点。
Platelet-derived growth factors (PDGF) have been implicated in kidney disease progression. We previously found that PDGF-C is upregulated at sites of renal fibrosis and that antagonism of PDGF-C reduces fibrosis in the unilateral ureteral obstruction model. We studied the role of PDGF-C in collagen 4A3−/−(“Alport”) mice, a model of progressive renal fibrosis with greater relevance to human kidney disease. Alport mice were crossbred with PDGF-C−/−mice or administered a neutralizing PDGF-C antibody. Both PDGF-C deficiency and neutralization reduced serum creatinine and blood urea nitrogen levels and mitigated glomerular injury, renal fibrosis, and renal inflammation. Unexpectedly, systolic blood pressure was also reduced in both Alport and wild-type mice treated with a neutralizing PDGF-C antibody. Neutralization of PDGF-C reduced arterial wall thickness in the renal cortex of Alport mice. Aortic rings isolated from anti-PDGF-C-treated wildtype mice exhibited reduced tension and faster relaxation than those of untreated mice.In vitro, PDGF-C upregulated angiotensinogen in aortic tissue and in primary hepatocytes and induced nuclear factor κB (NFκB)/p65-binding to the angiotensinogen promoter in hepatocytes. Neutralization of PDGF-C suppressed transcript expression of angiotensinogen in Alport mice and angiotensin II receptor type 1 in Alport and wildtype mice. Finally, administration of neutralizing PDGF-C antibodies ameliorated angiotensin II-induced hypertension in healthy mice. Thus, in addition to its key role in mediating renal fibrosis, we identified PDGF-C as a mediator of hypertension via effects on renal vasculature and on the renin-angiotensin system. The contribution to both renal fibrosis and hypertension render PDGF-C an attractive target in progressive kidney disease.
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影响因子：
14.9
作者：
Sanchez-Guerrero E;Midgley VC;Khachigian LM
通讯作者：
Khachigian LM
DOI：
10.1073/pnas.0409722102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Campbell, JS;Hughes, SD;Fausto, N
通讯作者：
Fausto, N
PDGF-C在胶质母细胞瘤模型中诱导血管成熟，并减弱对抗VEGF治疗的反应。
影响因子：
3.7
作者：
di Tomaso E;London N;Fuja D;Logie J;Tyrrell JA;Kamoun W;Munn LL;Jain RK
通讯作者：
Jain RK
影响因子：
8
作者：
Nakagawa, Naoki;Barron, Luke;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.
影响因子：
15.9
作者：
Gomez, Ivan G.;MacKenna, Deidre A.;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.