and Abstract Because the US population is living longer, the impact of advanced age on the kidney is highly clinically relevant. Kidney disease outcomes are worse in the older versus younger patient population s and the elderly comprise the largest group to initiate dialysis annually in the US. Recent attention in the aged kidney has been given to cells of renin lineage because of their two essential functions: their endocrine function of producing the body's supply of renin, and their adult progenitor function as facultative stem cells that transdifferentiate into cell fates that they partially or fully replace, including podocytes. The scope of the problem is that in addition to a decrease in total CoRL density in the aged kidney, both functions are also impaired with advancing age. From the standpoint of glomerular diseases typified by podocyte depletion, reduced CoRL progenitor function limits podocyte regeneration, and therefore repair in the aged kidney. We reported that aged CoRL undergo senescence, apoptosis, and DNA damage, with an increase in complement components and inflammatory cytokines, consistent with a chronic low-grade inflammatory state. Aged CoRL mitochondria have lower biogenesis and energy, but increased reactive oxygen species accumulation. The knowledge gap is identifying the mechanisms that cause these changes to CoRL in aged kidneys. Importantly, our data shows that superimposed glomerular disease compounds the aging phenotype as follows: when podocytes are depleted in young mice in experimental FSGS, the changes to the transcriptome in young CoRL are very similar to the changes in CoRL in the healthy aged kidney without disease. We propose that changes to CoRL in glomerular disease recapitulates and superimposes changes to CoRL in aged kidneys, and that this compounding effect worsens disease outcomes in aged populations. The unmet need is targeting the mechanisms that impair CoRL function in the aged kidney with disease, with the ultimate goal to minimize further injury to the aged kidney. To achieve this, the following specific aims are proposed: (1) Test the hypothesis that senescence impairs the facultative stem cell function of cells of renin lineage (CoRL) during aging. (2) Test the hypothesis that chronic inflammation reduces the endocrine phenotype and function of aged cells of renin lineage. (3) Test the hypothesis that mitochondrial changes in the aged kidney lowers the number of cells of renin lineage. The significance of these studies includes uncovering, for the first time, potential mechanisms whereby age impairs the CoRL endocrine phenotype and function, reduces CoRL progenitor function and lowers CoRL density. In doing so, we will identify targets to modify in disease states in the aged kidney that maintain the CoRL phenotype and enhance their functions. Innovations include identifying changes to a kidney cell (cells of renin lineage) following injury to another kidney cell (podocyte loss) in FSGS that recapitulate the aged phenotype, and that these superimposed changes are very detrimental to the aged kidney.
Because kidney disease outcomes are more severe in older patients, a more comprehensive understanding of the overlap of changes and mechanisms that occur during healthy kidney aging and kidney disease is needed. This grant focuses on how age impacts the kidneys ability to make renin and regenerate new cells (podocytes)