Background: Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on GFR via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyper-responsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Methods: Micropuncture was performed in 4 groups of Inactin-anesthetizedWistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg/kg QD SQ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing the loop of Henle so that proximal reabsorption (Jprox) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Results: Alone, DFMO or high salt reduced SNGFR and suppressed Jprox independent of -SNGFR. Suppression of Jprox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. Conclusion: Ornithine decarboxylase is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.