The Role of Renin-lineage Cells from the Juxtaglomerular Apparatus for Mesangial cell Regeneration after glomerular Injury

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In previous studies creating and using a triple transgenic mouse line, we have shown a novel regenerative mechanism, where renin-positive juxtaglomerular adult progenitor cells were recruited from the juxtaglomerular apparatus into glomeruli after severe mesangial cell injury. Hereby, upon entering the glomerulus these recruited cells lose their renin-positivity and differentiate into mesangial cells (de novo acquiring mesangial cell markers).In this grant proposal, the role / importance of this mechanism of precursor cell recruitment for mesangial cell regeneration after severe injury will be explored.To analyze the role of renin expression for precursor cell function, we created mice with a specific renin knockout in renin-positive adult progenitor cells via crossing our triple-transgenic mice (mRen-rtTAm2/LC-1/tdTomato) with mice carrying a floxed renin gene (mRen-rtTAm2/LC-1/tdTomato/Ren flox). To characterize the overall importance of renin-positive adult progenitor cells for glomerular repair, we will ablate these cells by cell type specific inducible expression of either diphtheria toxin A (mRen-rtTAm2/LC-1/tdTomato/DTA) or diphtheria toxin receptor (mRen-rtTAm2/LC-1/tdTomato/R-DTR) and subsequent stimulation. Furthermore, we will study mRen-rtTAm2/LC-1/Confetti mice to identify the clonality pattern (i.e. random, focal-segmental, centripetal) of renin-derived precursor cells during mesangial repopulation.The isolation, phenotypic characterization, and transcriptom analysis of renin-positive progenitor cells compared to normal mesangial cells, will further help us to better understand the potential and unique features of these cells. In perspective, the anticipated results from the present proposal will demonstrate the special features and potential of the renin-positive precursor cells and allow us to therapeutically use/manipulate them for an improvement of this regenerative mechanism in the future.