We have previously shown that 40% calorie restriction (CR) prevents renal injury 21 weeks after 5/6 nephrectomy (Nx) in rats, regardless of whether protein intake was concurrently restricted or not. Growth retardation appeared to be a necessary prerequisite for the protective effects of CR. To further study these mechanisms, we performed 5/6 Nx in male F344 rats and pair-fed them with a control diet (ad lib group) or a high protein diet restricted by 40% so that protein intake was similar, but calorie consumption was reduced (CR group). Four weeks after 5/6 Nx, when glomerulosclerosis had not yet developed, we compared various parameters as follows in both dietary groups and sham operated rats: urinary protein excretion (uPr), GFR (14C inulin clearance), mean nephron GFR (MNGFR; GFR divided by total number of glomeruli), glomerular volume (VG), tubulointerstitial index (TII), a measure of tubular damage kidney weight (kidney wt), kidney IGF-I content by RIA, and IGF-I immunohistochemistry. CR ameliorated the increase of MNGFR, but not glomerular hypertrophy. TU, kidney wt and kidney IGF-I content were increased in the ad lib Nx group; these changes were alleviated by CR. Two weeks after 5/6 Nx, immunohistochemistry for IGF-I showed increased staining in superficial distal nephrons in the ad lib group, and this was also suppressed by CR. The occurrence of tubulointerstitial pathology prior to glomerulosclerosis, and the beneficial effects of CR on all parameters except Vg indicate a dissociation of mechanisms which result in tubular versus glomerular hypertrophy and damage. Specifically, they suggest that tubular damage may occur secondarily to glomerular hyperfiltration and work-related tubular hypertrophy, rather than as a process of ischemia due to compromise of post glomerular circulation by glomerulosclerosis.
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