Urinary and Renal Tissue Kallikrein in the Streptozocin-diabetic Rat

Abstract

The renal kallikrein-kinin system is thought to participate in blood pressure regulation and displays abnormalities in human hypertension, as well as in many animal models of hypertension. Urinary excretion and tissue levels of renal kallikrein were measured in streptozocin (STZ)-diabetic rats in relation to blood pressure, glycemia, and insulin treatment.

In study 1, STZ-diabetic rats with marked hyperglycemia showed reduced kallikrein-like esterase excretion, compared with control rats, when first measured after 7 days of diabetes (9.9 ± 2.5 versus 17.5 ± 2.4 EU/24 h, P < 0.05). This difference increased with time and, after 210 days, urinary esterase excretion in diabetic and control rats was 6.7 ± 2.1 and 39.0 ± 6.0 EU/24 h, respectively (P < 0.001). Urine kallikrein, measured by radioimmunoassay, was similarly reduced in diabetic rats (40.4 ± 8.0 versus 88.0 ± 6.5 μg/24 h, at 30 days, P < 0.001). At 120 days, systolic blood pressures were elevated in diabetic rats (P < 0.05), and at 180 days over 60% of the diabetic rats had pressures above the highest pressures of control rats.

In study 2, STZ-diabetic rats were treated with insulin for 2 wk (2 U NPH at 0800 h, or 2 U NPH at 0800 and 1600 h). In the single-dose group, with hyperglycemia similar to that of diabetic rats in study 1, kallikrein excretion was reduced as early as day 2, compared with nondiabetic rats (56.0 ± 6.1 versus 109 ± 9.4 μg/24 h, respectively, P < 0.001). In the diabetic rats treated with twice-daily insulin, glycemia was reduced and daily urine glucose was not significantly different from that in controls. Kallikrein excretion was normal in these rats.

In study 3, we measured renal tissue kallikrein i untreated and insulin-treated (2.25 U PZI) STZdiabetic rats. After 2 wk, untreated diabetic rats had decreased renal kallikrein compared with nondiabetic rats (22.8 ± 1.6 versus 29.7 ± 1.4 ng/mg protein, P < 0.001). In the insulin-treated diabetic rats with near-normal plasma glucose levels, renal kallikrein (35.8 ± 2.1 ng/mg protein) was increased above that of untreated diabetic (P < 0.001) or nondiabetic rats (P < 0.05).

These studies confirm that STZ-diabetic rats develop systolic hypertension as assessed by tail cuff measurement. There is an early reduction in kallikrein excretion, which reflects reduced renal enzyme content. These abnormalities in kallikrein can be prevented by insulin treatment. Relationships of these changes in urinary and renal kallikrein to the function of the diabetic kidney and development of hypertension in this model can now be explored.