Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes.
In early diabetes, the kidney grows and the glomerular filtration rate (GFR) increases. This growth is linked to ornithine decarboxylase (ODC). The study of hyperfiltration has focused on microvascular abnormalities, but hyperfiltration may actually result from a prior increase in capacity for proximal reabsorption which reduces the signal for tubuloglomerular feedback (TGF). Experiments were performed in Wistar rats after 1 week of streptozotocin diabetes. Kidney weight, ODC activity, and GFR were correlated in diabetic and control rats given difluoromethylornithine (DFMO; Marion Merrell Dow, Cincinnati, Ohio, USA) to inhibit ODC. We assessed proximal reabsorption by micropuncture, using TGF as a tool for manipulating single-nephron GFR (SNGFR), then plotting proximal reabsorption versus SNGFR. ODC activity was elevated 15-fold in diabetic kidneys and normalized by DFMO, which also attenuated hyperfiltration and hypertrophy. Micropuncture data revealed an overall increase in proximal reabsorption in diabetic rats too great to be accounted for by glomerulotubular balance. DFMO prevented the overall increase in proximal reabsorption. These data confirm that ODC is required for the full effect of diabetes on kidney size and proximal reabsorption in early streptozotocin diabetes and are consistent with the hypothesis that diabetic hyperfiltration results from normal physiologic actions of TGF operating in a larger kidney, independent of any primary malfunction of the glomerular microvasculature.
Thomson
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SC
Department of Medicine, Division of Nephrology/Hypertension, University of California at San Diego and Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, California 92161-9151, USA. sthomson@ucsd.edu
Deng
A
A
Bao
D
D
Satriano
J
J
Blantz
R C
RC
Vallon
V
V
D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000503:physiopathology*; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D006984:Hypertrophy; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000503:physiopathology; D008297:Male; D009929:Organ Size; D009955:Ornithine Decarboxylase / Q000097:blood / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D010477:Perfusion; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; C019722:arginine decarboxylase; D000518:Eflornithine