Impaired SIRT1 activity leads to diminution in glomerular endowment without accelerating age-associated GFR decline

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD⁺ -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1^Y/Y ) mice had lower GFRs and fewer glomeruli than their wild-type (Sirt1^+/+ ) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1^Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1^Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.