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

Abstract

Miracle CM, Rieg T, Mansoury H, Vallon V, Thomson SC. Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt. Am J Physiol Renal Physiol 295: F995-F1002, 2008. First published June 18, 2008 doi:10.1152/ajprenal.00491.2007.-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 ⅐ kg Ϫ1 ⅐ day Ϫ1 ), 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 GLOMERULAR HYPERFILTRATION is a cardinal feature of early diabetes mellitus (5). Several lines of evidence support a tubular hypothesis to explain how glomerular filtration rate (GFR) comes to be elevated in early diabetes (reviewed in Ref. 17). According to this hypothesis, hyperfiltration is rooted in a prior increase in proximal reabsorption with GFR rising secondarily via negative feedback through the macula densa. In the course of trying to determine how the initial increase in proximal reabsorption comes about, we previously discovered that it could be prevented by suppressing growth of the kidney (15), which is normally rapid in early diabetes (10). We also discovered that proximal reabsorption in early diabetes is overly sensitive to dietary salt, to the extent that, when placed on a high salt diet, a diabetic rat drops its proximal reabsorption sufficiently to activate tubuloglomerular feedback (TGF), thereby reducing single nephron GFR (SNGFR) (20, 21). Since a reciprocal effect of dietary salt on GFR is contrary to usual expectation, we refer to this phenomenon as the salt paradox. So far, the salt parad...

The proximal tubule in the pathophysiology of the diabetic kidney

“…The diabetic proximal tubule, however, may have lost this characteristic of a differentiated nephron segment, and as a consequence, responds strongly to dietary NaCl, forming the basis for the salt paradox. Indeed, and supporting a role of diabetic kidney growth, pharmacological inhibition of ODC and tubular growth prevented the salt paradox (92).…”

Unexpected effect of angiotensin AT1receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy

“…Unless stated otherwise, results are presented as group means Ϯ SE as generated by least-squares ANOVA, which pools the variance and redistributes according to sample size. This form of presentation conceals intergroup differences in raw variance, which were computed by the Fmax test (11) and are discussed separately. In addition to ANCOVA a nonlinear logistical model was used to parse the role of GTB from data on proximal reabsorption.…”

“…Data from these paired collections were exploited to 1) determine SNGFR at both extremes of TGF activation, which gives the range for the TGF response, and 2) characterize proximal reabsorption as a function of SNGFR as a method of testing the efficiency of GTB and for revealing primary effects of STN with and without losartan on proximal reabsorption. Justification for this method of analyzing proximal reabsorption has been developed in previous publications (11,26,29).…”

Renal NMDA receptors independently stimulate proximal reabsorption and glomerular filtration

“…Tubular fluid samples were assayed for volume by transfer to a constant-bore glass capillary and then counted for radioactivity to determine SNGFR. Data from these paired collections were exploited to characterize J prox as a function of SNGFR by linear interpolation (12,26,28).…”

“…To test for primary effects on tubular reabsorption, one must control for differences in load delivered to the tubule by glomerular filtration. To accomplish this, we used tubuloglomerular feedback (TGF) as a tool for manipulating single-nephron GFR (SNGFR) so that J prox could be determined as a function of SNGFR in each nephron as previously described (12,26,28). Late proximal nephrons were localized on the kidney surface and an obstructing wax block was inserted immediately upstream from the most downstream accessible segment.…”