Dmitrieva Renata I, Hinojos Cruz A, Boerwinkle Eric, Braun Michael C, Fornage Myriam, Doris Peter A
Institute of Molecular Medicine, University of Texas HSC at Houston, TX 77030, USA.
Hypertension. 2008 Jun;51(6):1583-9. doi: 10.1161/HYPERTENSIONAHA.108.110163. Epub 2008 Apr 28.
Hypertension in spontaneously hypertensive rat (SHR) is associated with renal redox stress, and we hypothesized that nephropathy arises in SHR-A3 from altered capacity to mitigate redox stress compared with nephropathy-resistant SHR lines. We measured renal expression of redox genes in distinct lines of the spontaneously hypertensive rat (SHR-A3, SHR-B2, SHR-C) and the normotensive Wistar-Kyoto (WKY) strain. The SHR lines differ in either resisting (SHR-B2, SHR-C) or experiencing hypertensive nephropathy (SHR-A3). Immediately before the emergence of hypertensive renal injury expression of redox genes in SHR-A3 was profoundly altered compared with the injury-resistant SHR lines and WKY. This change appeared to arise in antioxidant genes where 16 of 28 were expressed at 34.3% of the level in the reference strain (WKY). No such change was observed in the injury-resistant SHR lines. We analyzed occurrence of transcription factor matrices in the promoters of the downregulated antioxidant genes. In these genes, the hepatocyte nuclear factor 1 (HNF1) transcription factor matrix was found to be nearly twice as likely to be present and the overall frequency of HNF1 sites was nearly 5 times higher, compared with HNF1 transcription factor matrices in antioxidant genes that were not downregulated. We identified 35 other (nonredox) renal genes regulated by HNF1. These were also significantly downregulated in SHR-A3, but not in SHR-B2 or SHR-C. Finally, expression of genes that comprise HNF1 (Tcf1, Tcf2, and Dcoh) was also downregulated in SHR-A3. The present experiments uncover a major change in transcriptional control by HNF1 that affects redox and other genes and precedes emergence of hypertensive renal injury.
自发性高血压大鼠（SHR）的高血压与肾脏氧化还原应激有关，我们推测，与抗肾病的SHR品系相比，SHR - A3中肾病的发生是由于减轻氧化还原应激的能力改变所致。我们测量了自发性高血压大鼠（SHR - A3、SHR - B2、SHR - C）和正常血压的Wistar - Kyoto（WKY）品系中氧化还原基因的肾脏表达。SHR品系在抗高血压肾病（SHR - B2、SHR - C）或患高血压肾病（SHR - A3）方面存在差异。在高血压肾损伤出现之前，与抗损伤的SHR品系和WKY相比，SHR - A3中氧化还原基因的表达发生了深刻变化。这种变化似乎出现在抗氧化基因中，28个基因中有16个基因的表达水平为参照品系（WKY）的34.3%。在抗损伤的SHR品系中未观察到这种变化。我们分析了下调的抗氧化基因启动子中转录因子矩阵的出现情况。与未下调的抗氧化基因中的肝细胞核因子1（HNF1）转录因子矩阵相比，在这些基因中，HNF1转录因子矩阵出现的可能性几乎高出一倍，HNF1位点的总频率高出近5倍。我们鉴定出另外35个受HNF1调控的（非氧化还原）肾脏基因。这些基因在SHR - A3中也显著下调，但在SHR - B2或SHR - C中未下调。最后，构成HNF1的基因（Tcf1、Tcf2和Dcoh）在SHR - A3中的表达也下调。本实验揭示了HNF1在转录调控方面的一个重大变化，该变化影响氧化还原基因和其他基因，并在高血压肾损伤出现之前发生。
