Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California Submitted 18 October 2007 ; accepted in final form 13 June 2008 Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (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 hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar 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 –1 ·day –1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption ( J prox ) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC 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. diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance Address for reprint requests and other correspondence: S. Thomson, Division of Nephrology-Hypertension, 3350 La Jolla Village Drive 9151, San Diego, CA 92161