Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt.
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 (Jprox) 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 Jprox independent of SNGFR. Suppression of Jprox 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.
Department of Medicine, Division of Nephrology-Hypertension, University of California and Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive 9151, San Diego, CA 92161, USA.
Cynthia M
CM
Miracle
Timo
T
Rieg
Hadi
H
Mansoury
Volker
V
Vallon
Scott C
SC
Thomson
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009929:Organ Size; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D014556:Urine
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D017673:Sodium Chloride, Dietary; D009955:Ornithine Decarboxylase; D000518:Eflornithine