title: Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease.
abstract: Modified vascular smooth muscle cells of the kidney afferent arterioles have recently been shown to serve as progenitors for glomerular epithelial cells in response to glomerular injury. To determine whether such cells of renin lineage (CoRL) serve as progenitors for other cells in kidney disease characterized by both glomerular and tubulointerstitial injury, permanent genetic cell fate mapping of adult CoRL using Ren1cCreER × Rs-tdTomato-R reporter mice was performed. TdTomato-labeled CoRL were almost completely restricted to the juxtaglomerular compartment in healthy kidneys. Following 2 wk of antibody-mediated focal segmental glomerulosclerosis (FSGS) or 16 wk of ⅚ nephrectomy-induced chronic kidney diseases, tdTomato-mapped CoRL were identified in both interstitial and glomerular compartments. In the interstitium, PDGFβ receptor (R)-expressing cells significantly increased, and a portion of these expressed tdTomato. This was accompanied by a decrease in native pericyte number, but an increase in the number of tdTomato cells that coexpressed the pericyte markers PDGFβ-R and NG2. These cells surrounded vessels and coexpressed the pericyte markers CD73 and CD146, but not the endothelial marker ERG. Within glomeruli of reporter mice with the ⅚ nephrectomy model, a subset of labeled CoRL migrated to the glomerular tuft and coexpressed podocin and synaptopodin. By contrast, labeled CoRL were not detected in glomerular or interstitial compartments following uninephrectomy. These observations indicate that in addition to supplying new adult podocytes to glomeruli, CoRL have the capacity to become new adult pericytes in the setting of interstitial disease. We conclude that CoRL have the potential to function as progenitors for multiple adult cell types in kidney disease.
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington; scoobie@uw.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pippin
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington;
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Kaverina
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington;
authors.forename: Diana G
authors.initials: DG
authors.lastname: Eng
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington;
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Krofft
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York; and.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Glenn
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington; Biogen IDEC, Cambridge, Massachusetts.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York; and.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Gross
authors.affiliation: Division of Nephrology, University of Washington, Seattle, Washington;
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000648:ultrastructure; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020286:Pericytes / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D050199:Podocytes / Q000378:metabolism* / Q000648:ultrastructure; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012083:Renin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D008164:Luminescent Proteins; D012083:Renin
keywords: FSGS; PDGFβ-R; interstitium; pericyte; podocyte; regeneration; remnant kidney; tubulointerstitium