Open AccessImpaired SIRT 1 activity leads to diminution in glomerular endowment without accelerating age‐associated GFR decline
Author(s) -
Bellin Ashley R.,
Zhang Yanling,
Thai Kerri,
Rosenblum Norman D.,
CullenMcEwen Luise A.,
Bertram John F.,
Gilbert Richard E.
Publication year - 2019
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14044
Subject(s) - endocrinology , medicine , glomerulosclerosis , sirtuin 1 , renal function , nephron , kidney , kidney disease , sirtuin , nad+ kinase , biology , chemistry , proteinuria , downregulation and upregulation , enzyme , biochemistry , gene
Glomerular filtration rate ( GFR ) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT 1 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 SIRT 1 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 SIRT 1 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 SIRT 1 inactivity on kidney aging. At 14 months of age, SIRT 1 catalytically inactive ( Sirt1 Y/Y ) mice had lower GFR s 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 SIRT 1 not only in determining nephron endowment but also in orchestrating the response to it.