The PPAR-gamma-binding sequence Pal3 is necessary for basal but dispensable for high-fat diet regulated human renin expression in the kidney
Tóm tắt
We reported earlier that PPAR-gamma regulates renin transcription through a human-specific atypical binding sequence termed hRen-Pal3. Here we developed a mouse model to investigate the functional relevance of the hRen-Pal3 sequence in vivo since it might be responsible for the increased renin production in obesity and thus for the development of accompanying arterial hypertension. We used bacterial artificial chromosome construct and co-placement strategy to generate two transgenic mouse lines expressing the human renin gene from identical genomic locus without affecting the intrinsic mouse renin expression. One line carried a wild-type hRen-Pal3 in the transgene (Pal3wt strain) and the other a mutated non-functional Pal3 (Pal3mut strain). Human renin expression was correctly targeted to the renin-producing juxtaglomerular (JG) cells of kidney in both lines. However, Pal3mut mice had lower basal human renin expression. Since human renin does not recognize mouse angiotensinogen as substrate, the blood pressure was not different between the strains. Stimulation of renin production with the angiotensin-converting enzyme inhibitor enalapril equipotentially stimulated the human renin expression in Pal3wt and Pal3mut mice. High-fat diet for 10 weeks which is known to activate PPAR-gamma failed to increase human renin mRNA in kidneys of either strain. These findings showed that the human renin PPAR-gamma-binding sequence hRen-Pal3 is essential for basal renin expression but dispensable for the cell-specific and high-fat diet regulated renin expression in the kidney.
Tài liệu tham khảo
Castrop H, Hocherl K, Kurtz A, Schweda F, Todorov V, Wagner C (2010) Physiology of kidney renin. Physiol Rev 90:607–673. doi:10.1152/physrev.00011.2009
Desch M, Schreiber A, Schweda F, Madsen K, Friis UG, Weatherford ET, Sigmund CD, Sequeira Lopez ML, Gomez RA, Todorov VT (2010) Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells. Hypertension 55:660–666. doi:10.1161/HYPERTENSIONAHA.109.138800
Desch M, Schubert T, Schreiber A, Mayer S, Friedrich B, Artunc F, Todorov VT (2010) PPARgamma-dependent regulation of adenylate cyclase 6 amplifies the stimulatory effect of cAMP on renin gene expression. Mol Endocrinol 24:2139–2151. doi:10.1210/me.2010-0134
Desch M, Harlander S, Neubauer B, Gerl M, Germain S, Castrop H, Todorov VT (2011) cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo. Pflugers Arch 461:567–577. doi:10.1007/s00424-011-0956-z
Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355–361. doi:10.1038/nm1025
Fukamizu A, Sugimura K, Takimoto E, Sugiyama F, Seo MS, Takahashi S, Hatae T, Kajiwara N, Yagami K, Murakami K (1993) Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem 268:11617–11621
Glenn ST, Jones CA, Gross KW, Pan L (2013) Control of renin [corrected] gene expression. Pflugers Arch 465:13–21. doi:10.1007/s00424-012-1110-2
Gomez RA, Lopez ML (2017) Plasticity of renin cells in the kidney vasculature. Curr Hypertens Rep 19:14. doi:10.1007/s11906-017-0711-8
Hackenthal E, Paul M, Ganten D, Taugner R (1990) Morphology, physiology, and molecular biology of renin secretion. Physiol Rev 70:1067–1116
Hall JE (2003) The kidney, hypertension, and obesity. Hypertension 41:625–633. doi:10.1161/01.HYP.0000052314.95497.78
Hatae T, Takimoto E, Murakami K, Fukamizu A (1994) Comparative studies on species-specific reactivity between renin and angiotensinogen. Mol Cell Biochem 131:43–47
Kasper DL, Harrison TR (2005) Harrison’s principles of internal medicine, 16th edn. McGraw-Hill, Medical Pub. Division, New York
Lee G, Saito I (1998) Role of nucleotide sequences of loxP spacer region in Cre-mediated recombination. Gene 216:55–65
Lemberger T, Desvergne B, Wahli W (1996) Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 12:335–363. doi:10.1146/annurev.cellbio.12.1.335
Matsushita K, Morello F, Wu Y, Zhang L, Iwanaga S, Pratt RE, Dzau VJ (2010) Mesenchymal stem cells differentiate into renin-producing juxtaglomerular (JG)-like cells under the control of liver X receptor-alpha. J Biol Chem 285:11974–11982. doi:10.1074/jbc.M109.099671
Mayer S, Roeser M, Lachmann P, Ishii S, Suh JM, Harlander S, Desch M, Brunssen C, Morawietz H, Tsai SY, Tsai MJ, Hohenstein B, Hugo C, Todorov VT (2012) Chicken ovalbumin upstream promoter transcription factor II regulates renin gene expression. J Biol Chem 287:24483–24491. doi:10.1074/jbc.M111.329474
Merrill DC, Thompson MW, Carney CL, Granwehr BP, Schlager G, Robillard JE, Sigmund CD (1996) Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest 97:1047–1055. doi:10.1172/JCI118497
Okuno M, Arimoto E, Ikenobu Y, Nishihara T, Imagawa M (2001) Dual DNA-binding specificity of peroxisome-proliferator-activated receptor gamma controlled by heterodimer formation with retinoid X receptor alpha. Biochem J 353:193–198
Shimizu T, Oishi T, Omori A, Sugiura A, Hirota K, Aoyama H, Saito T, Sugaya T, Kon Y, Engel JD, Fukamizu A, Tanimoto K (2005) Identification of cis-regulatory sequences in the human angiotensinogen gene by transgene coplacement and site-specific recombination. Mol Cell Biol 25:2938–2945. doi:10.1128/MCB.25.8.2938-2945.2005
Siegal ML, Hartl DL (1996) Transgene Coplacement and high efficiency site-specific recombination with the Cre/loxP system in Drosophila. Genetics 144:715–726
Tanimoto K, Sugiura A, Kanafusa S, Saito T, Masui N, Yanai K, Fukamizu A (2008) A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation. J Clin Invest 118:1006–1016. doi:10.1172/JCI33824
Todorov VT (2013) PPARgamma-dependent control of renin expression: molecular mechanisms and pathophysiological relevance. PPAR Res 2013:451016. doi:10.1155/2013/451016
Todorov VT, Desch M, Schmitt-Nilson N, Todorova A, Kurtz A (2007) Peroxisome proliferator-activated receptor-gamma is involved in the control of renin gene expression. Hypertension 50:939–944. doi:10.1161/HYPERTENSIONAHA.107.092817
Todorov VT, Desch M, Schubert T, Kurtz A (2008) The Pal3 promoter sequence is critical for the regulation of human renin gene transcription by peroxisome proliferator-activated receptor-gamma. Endocrinology 149:4647–4657. doi:10.1210/en.2008-0127
Westerbacka J, Kolak M, Kiviluoto T, Arkkila P, Siren J, Hamsten A, Fisher RM, Yki-Jarvinen H (2007) Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 56:2759–2765. doi:10.2337/db07-0156
Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund CD (1994) Functional expression of the human angiotensinogen gene in transgenic mice. J Biol Chem 269:32497–32502
Zanchi A, Chiolero A, Maillard M, Nussberger J, Brunner HR, Burnier M (2004) Effects of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men. J Clin Endocrinol Metab 89:1140–1145