Role of PPARgamma in the regulation of renin gene expression: from molecule to organism
Final Report Abstract
Previous cell culture findings suggested that PPARgamma influences renin transcription in a species-dependent manner and that the human renin gene is more sensitive to PPARgamma than the mouse renin gene. A newly described human-specific renin Pal3 (hRen-Pal3) sequence was identified to be the main cause for this discrepancy. Moreover, the in vitro data opened the intriguing possibility that activated PPARgamma stimulates the renin production during obesity, thus acting pro-hypertensively. Therefore this project aimed to investigate the role of nuclear receptor PPARgamma in the transcriptional control of the renin gene with special focus on in vivo mouse models. Additional aspects included the role COUP-TFII in the control of renin gene and the development of a strategy to selectively target the renin-producing cells in kidney. Further characterization of the molecular mechanisms of the hRen-Pal3 regulated gene expression revealed that this sequence is causally involved in the cAMP-dependent regulation of renin gene expression by binding CREB. This was important finding since cAMP/PKA/CREB signaling is the central pathway controlling the expression of renin. Experiments with transgenic mice showed that in renin-producing cells PPARgamma does not play decisive role for the blood pressure control during high-fat diet which represents a model for obesity in man. Newly generated humanized renin mouse strains were used to demonstrate that the hRen-Pal3 sequence is necessary for the basal expression of human renin gene in accordance to the earlier cell culture studies. However, involvement of the hRen-Pal3 motif in the up-regulation of human renin production in the high-fat model of obesity could not be established with the same transgenic model. Thus the PPARgamma binding sequence hRen-Pal3 was found to be relevant only for the constitutive expression of human renin in vivo. The novel humanized renin transgenic mouse strains clearly demonstrated that there are speciesspecific differences in the molecular control of renin production. Therefore these strains could be used as a basis for the creation of mice with completely humanized renin-angiotensin system (RAS). Such mouse model could become of general importance since RAS is central player in the control of blood pressure and pathogenesis of organ damage.
Publications
- Chicken ovalbumin upstream promoter transcription factor II regulates renin gene expression. J Biol Chem 287:24483-24491, 2012
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
(See online at https://doi.org/10.1074/jbc.M111.329474) - PPARgamma-dependent control of renin expression: Molecular mechanisms and pathophysiological relevance. PPAR Research, ID 451016, 2013
Todorov VT
(See online at https://doi.org/10.1155/2013/451016) - Lineage Cells Repopulate the Glomerular Mesangium after Injury. J Am Soc Nephrol 26:48-54, 2015
Starke C, Betz H, Hickmann L, Lachmann P, Neubauer B, Kopp JB, Sequeira-Lopez ML, Gomez RA, Hohenstein B, Todorov VT, Hugo C. Renin
(See online at https://doi.org/10.1681/ASN.2014030265)
