Phlorizin-induced glycosuria does not prevent gentamicin nephrotoxicity in rats

TY - JOUR

T1 - Phlorizin-induced glycosuria does not prevent gentamicin nephrotoxicity in rats

AU - Gouvea, W. L.

AU - Alpert, H. C.

AU - Kelley, J.

AU - Pardo, V.

AU - Vaamonde, C. A.

PY - 1989/1/1

Y1 - 1989/1/1

N2 - Because rats with streptozotocin-induced diabetes mellitus (DM) have a high solute diuresis (glycosuria of 10 to 12 g/day), we have suggested that this may in part be responsible for their resistance to gentamicin-induced acute renal failure (ARF). The protection from gentamicin nephrotoxicity was studied in non-diabetic rats with chronic solute diuresis induced by blockage of tubular glucose reabsorption with phlorizin (P). DM rats with mild glycosuria (similar in degree to that of the P treated animals) were also studied. Unanesthetized adult female, Sprague-Dawley rats were divided in four groups and studied for 15 days. Group 1 (P alone) received P, 360 mg/day, for 15 days; Group II (P + gentamicin); Group III (gentamicin alone) and Group IV (mild DM + gentamicin). Nephrotoxic doses (40 mg/kg body wt/day) of gentamicin were injected during the last nine days of study to the animals of group II to IV. In Group I, P induced a moderate and stable glycosuria (3.9 ± 0.1 g/day, SE), and no functional or morphologic evidence of renal dysfunction (baseline C(Cr) 2.1 ± 0.1 ml/min, undetectable lysozymuria) or damage (tubular necrosis score [maximum 4], zero). In Group II, P did not prevent gentamicin-ARF (maximal decrease in C(Cr) at day 9, 89%, P < 0.001; peak lysozymuria, 1863 ± 321 μg/day; and tubular necrosis score, 3.9 ± 0.1). These values were not different from those of Group III: maximal decrease in C(Cr) 73% (P < 0.001); lysozymuria, 2147 ± 701 μg/day; tubular necrosis score, 3.8 ± 0.1. In marked contrast, Group IV DM rats with mild glycosuria (4.1 ± 1.0 g/day) were protected from gentamicin toxicity: maximal decrease in C(Cr) was 10% (from 2.0 ± 0.1 to 1.8 ± 0.1 ml/min; P < 0.001 vs. Groups II and III); peak lysozymuria, 31 ± 31 μg/day (P < 0.001 vs. Groups II and III); tubular necrosis score, 0.8 ± 0.4 (P < 0.001 vs. Groups II and III). No differences in renal cortical gentamicin accumulation were found between Groups II, III and IV (360 ± 20, 395 ± 25 and 493 ± 55 μg/g wet tissue, respectively). The later finding most likely resulted from an underestimation of gentamicin tissue levels in Groups II and III due to tubular necrosis. We conclude that P alone does not result in renal dysfunction or damage. The protection against gentamicin-ARF of DM rats with mild glycosuria, and the lack of protection in the P + G treated rats were independent of the glycosuria, solute diuresis and urine flow rate. Thus, the resistance afforded by the diabetic state to gentamicin-ARF is not explained by the enhanced solute diuresis or altered glucose transport.

AB - Because rats with streptozotocin-induced diabetes mellitus (DM) have a high solute diuresis (glycosuria of 10 to 12 g/day), we have suggested that this may in part be responsible for their resistance to gentamicin-induced acute renal failure (ARF). The protection from gentamicin nephrotoxicity was studied in non-diabetic rats with chronic solute diuresis induced by blockage of tubular glucose reabsorption with phlorizin (P). DM rats with mild glycosuria (similar in degree to that of the P treated animals) were also studied. Unanesthetized adult female, Sprague-Dawley rats were divided in four groups and studied for 15 days. Group 1 (P alone) received P, 360 mg/day, for 15 days; Group II (P + gentamicin); Group III (gentamicin alone) and Group IV (mild DM + gentamicin). Nephrotoxic doses (40 mg/kg body wt/day) of gentamicin were injected during the last nine days of study to the animals of group II to IV. In Group I, P induced a moderate and stable glycosuria (3.9 ± 0.1 g/day, SE), and no functional or morphologic evidence of renal dysfunction (baseline C(Cr) 2.1 ± 0.1 ml/min, undetectable lysozymuria) or damage (tubular necrosis score [maximum 4], zero). In Group II, P did not prevent gentamicin-ARF (maximal decrease in C(Cr) at day 9, 89%, P < 0.001; peak lysozymuria, 1863 ± 321 μg/day; and tubular necrosis score, 3.9 ± 0.1). These values were not different from those of Group III: maximal decrease in C(Cr) 73% (P < 0.001); lysozymuria, 2147 ± 701 μg/day; tubular necrosis score, 3.8 ± 0.1. In marked contrast, Group IV DM rats with mild glycosuria (4.1 ± 1.0 g/day) were protected from gentamicin toxicity: maximal decrease in C(Cr) was 10% (from 2.0 ± 0.1 to 1.8 ± 0.1 ml/min; P < 0.001 vs. Groups II and III); peak lysozymuria, 31 ± 31 μg/day (P < 0.001 vs. Groups II and III); tubular necrosis score, 0.8 ± 0.4 (P < 0.001 vs. Groups II and III). No differences in renal cortical gentamicin accumulation were found between Groups II, III and IV (360 ± 20, 395 ± 25 and 493 ± 55 μg/g wet tissue, respectively). The later finding most likely resulted from an underestimation of gentamicin tissue levels in Groups II and III due to tubular necrosis. We conclude that P alone does not result in renal dysfunction or damage. The protection against gentamicin-ARF of DM rats with mild glycosuria, and the lack of protection in the P + G treated rats were independent of the glycosuria, solute diuresis and urine flow rate. Thus, the resistance afforded by the diabetic state to gentamicin-ARF is not explained by the enhanced solute diuresis or altered glucose transport.

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M3 - Article

C2 - 2709684

AN - SCOPUS:0024593589

VL - 35

SP - 1041

EP - 1048

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 4

ER -