Sex differences in transcriptomic profiles in aged kidney cells of renin lineage

Abstract

Renin expressing cells in the kidney’s juxta-glomeruluar compartment likely also serve as progenitors for adult glomerular cells in disease. Although these cells of renin lineage (CoRL) decrease in number with advancing kidney age, accompanied by less responsiveness to typical stimuli such as ACE-inhibition, mechanisms and the impact of sex as a biological variable with age are not known. Accordingly, labeled CoRL were sorted from individual young (2m) and aged (27m) male and female Ren1cCre|ZsGreen reporter mice, and their transcriptomic profiles analyzed by RNA seq. When both aged female and male mice were combined, there were 48 differentially expressed genes (DEG) compared to young mice. However, when compared to their young sex-matched mice, aged female and male mice had 159 and 503 DEGs respectively. In addition to marked differences in individual genes between aged female and male mice, gene ontology analysis showed major pathway differences by sex. The majority of DEGs in one sex did not significantly change or changed in the opposite direction in the other sex. These results show that in CoRL of advanced age, individual genes and gene ontologies change, but differ between female and male mice, highlighting sex related differences the aging process.

Global transcriptomic changes occur in aged mouse podocytes

“…This pattern of expression contrasts with the kidney aging of cells of renin lineage, for which most aging-associated genes are sex-specific. 7 Taken together, our findings indicate that the decreased expression of canonical podocyte marker genes, junctional and adhesion proteins, and pro-survival pathways synergize with the increase of inflammatory response pathways to provide a comprehensive mechanistic foundation for the well-established decrease in podocyte number and function with aging.…”

“…ith an aging population, attention has increasingly focused on age-associated changes in many different organs. Several predictable glomerular changes occur in the aged human, 1,2 canine, 3 rat, [4][5][6] and mouse [7][8][9][10] kidneys, including fibrosis and hypertrophy, and changes to parietal epithelial cells, [11][12][13][14] and podocytes. 4,5,[15][16][17] What is increasingly clear is that the decline in kidney function with aging cannot be solely explained by nephrosclerosis per se.…”

Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

“…However, we have shown that both sources of podocyte progenitors are adversely impacted by advancing age. For example, their numbers decrease with age leading to a reduced reservoir available to perform progenitor functions [ 19 , 29 ], they lose some of their characteristic markers, acquire phenotypic changes [ 19 , 30 ], and their expected responses to stimuli are reduced, such as the response of cells of renin lineage to RAAS blockade [ 31 ].…”

Mechanisms of Scarring in Focal Segmental Glomerulosclerosis

“…Renin lineage cells can migrate to Bowman's capsule or to the glomerular tuft, replacing PECs, podocytes, and mesangial cells after podocyte injury. [78][79][80] This repair capacity is remarkable because podocytes are normally derived from cap mesenchyme cells, whereas renin lineage cells derive from Foxd1 + stromal cells. Similar to PECs, renin + progenitor cells can differentiate either to podocytes, contributing to repair, or to activated mesangial cells, contributing to matrix secretion.…”