Female and male aging gene dynamics are different. (A) Female-centric perspective. Expression pattern of aged female vs. young female
DEGs (n=159) across all age and sex conditions. Group A genes (comprises 59.4% of all DEGs) are significantly up-regulated in aged vs.
young female, but do not have any significant change in aged vs. young male. Group B genes decreased in both aged vs. young female
and aged vs. young male. Group C genes show the opposite trend, as they are down-regulated in aged vs. young female, but up-regulated
in aged vs. young male. (B) Male-centric perspective. Expression pattern of aged male vs. young male DEGs (n=503) across all age and sex
conditions. Group A genes (comprises 9.7% of all DEGs) are up-regulated in aged vs. young male and are also moderately up-regulated in
aged vs. young female. Group B genes are significantly down-regulated in aged vs. young male are up-regulated in aged female mice.
Detection of renin lineage cell transdifferentiation to podocytes in the kidney glomerulus with dual lineage tracing
Eng DG, Kaverina NV, Schneider RRS, Freedman BS, Gross KW, Miner JH, Pippin JW, Shankland SJ
Dual reporting CoRL-PODO mice (Ren1cCreER/tdTomato/Nphs1-FLPo/FRT-EGFP) express tdTomato (red) in Cells of Renin
Lineage (CoRL)and EGFP (green) in Podocytes. In our model of experimental FSGS, we show for the first time that two distinct
cell types can be simultaneously labeled in the kidney and provide strong genetic evidence in vivo that lost podocytes can be
replaced in part by CoRL.
Lineage Tracing Aged Mouse Kidneys Shows Lower Number of Cells of Renin Lineage and Reduced Responsiveness to RAAS Inhibition
Hamatani H, Eng DG, Kaverina NV, Gross KW, Freedman, BS, Pippin JW, Shankland SJ
Cells of renin lineage (CoRL) (light orange) surrounding the afferent arteriole (depicted by orange circle) in the juxtaglomerular
compartment in young mice were permanently labeled with td-tomato (red) following the administration of tamoxifen at a young
In young mice, total CoRL number increased following RAAS inhibition with enalapril or losartan, due to both proliferation (purple)
and recruitment (green). CoRL number decreased between the ages of 3.5 months (=age 20 years in Humans) and 24m (= age 70
years in Humans), accompanied by, and perhaps due to, increased apoptotic genes such as Programmed Cell Death 6. In aged mice
given enalapril or losartan, CoRL recruitment was detected (green), but proliferation was barely detected (just one purple cell),
leading to a smaller increase in the overall CoRL population.
We propose that the lack of proliferation in aged CoRL might be due to CoRL senescence with increased pro-scenescent genes
(p16INK4a, Lamin A and B), and reduced proliferation due to increased cell cycle inhibition by Thioredoxin-interacting protein.
Charting the transcriptional landscape of cells of renin lineage following podocyte depletion
McClelland AD, Lichtnekert J, Eng DG, Pippin JW, Gross KW, Gharib SA, Shankland SJ
There is strong evidence that Cells of Renin Lineage (CoRL) are a nascent source of progenitor cells winthin the kidney. These cells
have been demonstrated to move away from the juxtaglomerular apparatus onto the Bowmans' capsule and the glomerular tuft
here they de novo express markers of parietal epithelial cells and podocytes respectively.
In order to gain a broad understanding of this process, we performed microarray analysis of isolated CoRL following depletion of
podocytes in a mouse model of Focal Segmental Glomerulosclerosis (FSGS), a disease marked by podocyte loss. In times of abrupt
podocyte loss, it was found that a CoRL undergo distinct changes in gene expression which can be broadly classified into two
broadly defined categories. These changesare also regulated by a small set of transcription factors, proteins that control the
expression activity of certain genes.
In the image above, is a representation of the relationship between changes in gene activity (clustered by pathway in the right half
of eachpanel) and transcription factors (the left half of each panel). The thickness of the ribbons connecting the left and right half
of each panel represent the number of genes within a pathway which are targets of a given transcription factor. In the left panel, a
number of pathways related to mitochondrial metabolic processes are listed along with transcription factors which target genes
within these pathways. These pathways are putitively downregulated according to gene-set enrichment analysis testing.
Conversely, the right panel depicts pathways involved in inflammatory signalling and transcription factors associated with them.
Collectively, these data demonstrate gross upregulated of inflammatory responses and downregulation of metabolic processes
which may indicate an stress/activation state and an increase in phenotypic plasticity respectively.
WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion
Kaverina NV, Eng DG, Largent AD, Daehn I, Chang A, Gross KW, Pippin JW, Hohenstein P, Shankland SJ
Cells of renin lineage (CoRL) begin to de novo express the podocyte markers in enalapril treated RenWt1 +/+ mice at D28 of
FSGS following podocyte depletion. Representative image of three color staining for podocin (podocyte marker, green), RFP
identifies td-Tomato-labeled CoRL, red) and DAPI.(nuclear, blue).