Highlight on Papers
Dr. Stuart Shankland - PubMed
Sex differences in transcriptomic profiles in aged
kidney cells of renin lineage
Wang Y, Eng DG, Pippin JW, Gharib SA, McClelland A, Gross KW, Shankland SJ
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-regulatedin aged vs. young male. (B) Male-centric perspective. Expression pattern of aged male
vs. young male DEGs (n=503) across all age and sexconditions. 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 age.
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-
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).