Hepatocyte nuclear factor 1 and hypertensive nephropathy.

TitleHepatocyte nuclear factor 1 and hypertensive nephropathy.
Publication TypeJournal Article
Year of Publication2008
AuthorsDmitrieva, RI, Hinojos, CA, Boerwinkle, E, Braun, MC, Fornage, M, Doris, PA
JournalHypertension
Volume51
Issue6
Pagination1583-9
Date Published2008 Jun
ISSN1524-4563
KeywordsAnimal Feed, Animals, Blood Pressure, Gene Expression Profiling, Hepatocyte Nuclear Factor 1, Hypertension, Renal, Kidney, Male, Oxidation-Reduction, Oxidative Stress, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Transcription, Genetic
Abstract

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.

DOI10.1161/HYPERTENSIONAHA.108.110163
Alternate JournalHypertension
PubMed ID18443232
PubMed Central IDPMC2840399
Grant ListR01 DK069632-03 / DK / NIDDK NIH HHS / United States
R01 DK045538 / DK / NIDDK NIH HHS / United States
R01 DK045538-10 / DK / NIDDK NIH HHS / United States
DDK74680 / / PHS HHS / United States
HL51021 / HL / NHLBI NIH HHS / United States
DDK45538 / / PHS HHS / United States
R01 DK069632 / DK / NIDDK NIH HHS / United States
R37 HL051021 / HL / NHLBI NIH HHS / United States