Does the mTOR system regulate the renin progenitor cell niche of the juxtaglomerular apparatus under physiological conditions and after mesangial cell injury?

• Applicant: Professor Dr. Christian Hugo
• Subject Area: Nephrology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416522779

By creation of specific transgenic mouse models, we could verify in previous publications that recruitment of renin-positive progenitor cells from a juxtaglomerular cell niche is important for mesangial cell repopulation and healing after mesangial cell injury. The progenitor cells lose their renin positivity when entering the intraglomerular area and start to express de novo typical mesangial marker proteins. Hereby, it is completely unknown which signals in the renin cells are important for intraglomerular recruitment and immigration.An unbiased approach to characterize the renin lineage cells via transcriptome analysis before and during our regeneration model in particular identified the mTORC1 activator protein Rheb as the possible trigger for the renin cells to start immigration into the glomerulus after injury. This finding is also supported by many additional pilot experiments for this grant application.According to our various pilot data, in this grant application the main hypothesis will be tested that mTORC1 activation is one central cellular signal in the juxtaglomerular renin-lineage cells which is necessary for recruitment and immigration of these cells into the glomerulus to arrange a successful repair after mesangial cell injury. Concurrently, we will also examine the local role of the mTOR system in regulating/maintaining the glomerular progenitor cell niche not only during regeneration after mesangiolysis but also under physiological conditions, since mTOR is known to be involved in cell death/survival of other precursor cell niches as well. Hereby, we explore the effects of specific raptor (mTORC1 pathway) or rictor (mTORC2 pathway) deficiency or both in renin-positive precursor cells of the juxtaglomerular apparatus, as well as a genetically induced (TSC-1 deficiency) hyperactivation of mTORC1, possibly leading to an uncontrolled increase/modification of the juxtaglomerular cell niche or even an uncontrolled recruitment towards intraglomerular sites. In addition, the effects of local renal mTOR modulations are compared with a systemic mTORC1 blockade via everolimus by confocal microscopy of kidney sections and longitudinally via daily intravital microscopy of the immigration process of the labelled renin lineage cells. The answers to these questions are supposed to influence the important mTOR system in a more differentiated way in the future as just continuing systemic mTOR blockade. The pathways influenced by mTOR modulation in the renin precursor cells can be further differentiated by transcriptome and proteome analysis (outcome-dependent) to develop more specific targets for future studies. Using renin specific cell lines the phenotypic changes/effects of mTOR modulation will be characterized. Furthermore, mTOR activation in the juxtaglomerular niche and intraglomerular area will be investigated in different human renal diseases to explore potential relevance for human disease.

• DFG Programme: Research Grants