Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging.
Podocyte depletion plays a major role in focal segmental glomerular sclerosis (FSGS). Because cells of the renin lineage (CoRL) serve as adult podocyte and parietal epithelial cell (PEC) progenitor candidates, we generated Ren1cCre/R26R-ConfettiTG/WT and Ren1dCre/R26R-ConfettiTG/WT mice to determine CoRL clonality during podocyte replacement. Four CoRL reporters (GFP, YFP, RFP, CFP) were restricted to cells in the juxtaglomerular compartment (JGC) at baseline. Following abrupt podocyte depletion in experimental FSGS, all four CoRL reporters were detected in a subset of glomeruli at day 28, where they co-expressed de novo four podocyte proteins (podocin, nephrin, WT-1 and p57) and two glomerular parietal epithelial cell (PEC) proteins (claudin-1, PAX8). To monitor the precise migration of a subset of CoRL over a 2w period following podocyte depletion, intravital multiphoton microscopy was used. Our findings demonstrate direct visual support for the migration of single CoRL from the JGC to the parietal Bowman's capsule, early proximal tubule, mesangium and glomerular tuft. In summary, these results suggest that following podocyte depletion, multi-clonal CoRL migrate to the glomerulus and replace podocyte and PECs in experimental FSGS.
Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, United States of America.
Natalya V
NV
Kaverina
Department of Physiology & Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America.|Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.
Hiroyuki
H
Kadoya
Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, United States of America.
Diana G
DG
Eng
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, United States of America.
Michael E
ME
Rusiniak
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
Maria Luisa S
ML
Sequeira-Lopez
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
R Ariel
RA
Gomez
Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, United States of America.
Jeffrey W
JW
Pippin
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, United States of America.
Kenneth W
KW
Gross
Department of Physiology & Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America.
Janos
J
Peti-Peterdi
Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, United States of America.
Stuart J
SJ
Shankland
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D002465:Cell Movement; D062445:Claudin-1 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000069416:Intravital Microscopy; D007678:Kidney Glomerulus / Q000166:cytology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D000072636:PAX8 Transcription Factor / Q000378:metabolism; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013269:Stochastic Processes; D025721:WT1 Proteins
C493965:Cdkn1c protein, mouse; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D000072636:PAX8 Transcription Factor; C499496:Pax8 protein, mouse; D012097:Repressor Proteins; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; C113267:nephrin; D012083:Renin