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 st udy of hyperfiltration has focused on microvascular abnormalities, but hype rfiltration may actually result from a prior increase in capacity for proxi mal reabsorption which reduces the signal for tubuloglomerular feedback (TG F). Experiments were performed in Wistar rats after 1 week of streptozotoci n diabetes. Kidney weight, ODC activity, and GFR were correlated in diabeti c and control rats given difluoromethylornithine (DFMO; Marion Merrell Dow, Cincinnati, Ohio, USA) to inhibit ODC. We assessed proximal reabsorption b y micropuncture, using TGF as a tool for manipulating single-nephron GFR (S NGFR), then plotting proximal reabsorption versus SNGFR ODC activity was el evated 15-fold in diabetic kidneys and normalized by DFMO, which also atten uated hyperfiltration and hypertrophy. Micropuncture data revealed an overa ll increase in proximal reabsorption in diabetic rats too great to be accou nted for by glomerulotubular balance. DFMO prevented the overall increase i n proximal reabsorption. These data confirm that ODC is required for the fu ll effect of diabetes on kidney size and proximal reabsorption in early str eptozotocin diabetes and are consistent with the hypothesis that diabetic h yperfiltration results from normal physiologic actions of TGF operating in a larger kidney, independent of any primary malfunction of the glomerular m icrovasculature.