Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes - PubMed (original) (raw)

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Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes

S C Thomson et al. J Clin Invest. 2001 Jan.

Abstract

In early diabetes, the kidney grows and the glomerular filtration rate (GFR) increases. This growth is linked to ornithine decarboxylase (ODC). The study of hyperfiltration has focused on microvascular abnormalities, but hyperfiltration may actually result from a prior increase in capacity for proximal reabsorption which reduces the signal for tubuloglomerular feedback (TGF). Experiments were performed in Wistar rats after 1 week of streptozotocin diabetes. Kidney weight, ODC activity, and GFR were correlated in diabetic and control rats given difluoromethylornithine (DFMO; Marion Merrell Dow, Cincinnati, Ohio, USA) to inhibit ODC. We assessed proximal reabsorption by micropuncture, using TGF as a tool for manipulating single-nephron GFR (SNGFR), then plotting proximal reabsorption versus SNGFR. ODC activity was elevated 15-fold in diabetic kidneys and normalized by DFMO, which also attenuated hyperfiltration and hypertrophy. Micropuncture data revealed an overall increase in proximal reabsorption in diabetic rats too great to be accounted for by glomerulotubular balance. DFMO prevented the overall increase in proximal reabsorption. These data confirm that ODC is required for the full effect of diabetes on kidney size and proximal reabsorption in early streptozotocin diabetes and are consistent with the hypothesis that diabetic hyperfiltration results from normal physiologic actions of TGF operating in a larger kidney, independent of any primary malfunction of the glomerular microvasculature.

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Figures

Figure 1

Figure 1

Framework for interactions between glomerulus and proximal tubule and pathways to hyperfiltration. VLP, late proximal flow. SNGFR and VLP are linked by TGF (sigmoid curves) and GTB (straight lines) which intersect at a single operating point. The operating point cannot change unless there is a change in TGF or GTB. Hyperfiltration can result from a shift in TGF (left panel) or an increase in proximal reabsorption (center panel). A primary increase in proximal reabsorption can induce TGF to reset thus obscuring increased reabsorption as the primary cause of hyperfiltration (right panel).

Figure 2

Figure 2

GFR vs. kidney weight in diabetic and control rats ± treatment with DFMO. GFR is for two kidneys. Kidney weight is wet-weight of left kidney. Dashed lines are 95% confidence intervals for linear regression. _r_2 = 0.996.

Figure 3

Figure 3

Activities of ODC and ADC in control and diabetic rats. A_P_ < 0.05 vs. control.

Figure 4

Figure 4

Pairwise intergroup comparisons of different indices of proximal reabsorption, each shown as a function of SNGFR. Line segments connect data obtained at minimum (higher SNGFR) and maximum (lower SNGFR) TGF activation. Group mean ± SEM is also shown in Table 2. Statistical significance of intergroup differences are described in the text for the regions of overlapping SNGFR. (a) Effects of diabetes. (b) Effects of DFMO in diabetes. (c) Effects of DFMO in controls. (d) Diabetes + DFMO vs. control + DFMO. DM, diabetes mellitus; Con, control.

Figure 5

Figure 5

Autoregulation of tubular reabsorption by GTB. Refer to text for formula of index. Index is unity when fractional reabsorption is constant across SNGFR. Index is zero when net reabsorption is constant across SNGFR. A_P_ < 0.05 vs. control. B_P_ < 0.05 vs. diabetes.

Figure 6

Figure 6

A working model to account for the effects of DFMO in the present study. The effects denoted with question marks have been demonstrated in cell culture (see text for references), but remain to be confirmed in diabetic animals.

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