Abstract P246: Increased Urinary Prorenin and sPRR Excretion in Early Type 1 Diabetes

Abstract

Activation of the intra-renal, rather than systemic renin angiotensin system (RAS) has been suggested to play a role in the development of diabetic kidney disease. In this study, we examined plasma and urinary prorenin/renin levels and urinary soluble prorenin receptor (sPRR) levels in a murine model of Type 1 diabetes. Male C57BL/6 mice were injected with streptozotocin (STZ) 50mg/kg at 3 months of age and metabolic balance studies conducted at 6 and 10 weeks post-injection. STZ injected mice developed hyperglycemia within 4 weeks of injection (STZ: 335 ± 35 vs control: 145 ± 22 mg/dL) and remained hyperglycemic at 10 weeks. At 10 weeks post-injection, STZ injected mice had significant polyuria (STZ: 20.9 ± 5.9 vs controls 1.8 ± 0.4 ml/day), increased water intake (STZ: 26.2 ± 5.9 vs controls: 6.2 ± 0.9 ml/day) and lower body weight (STZ: 28.3 ± 1.3 vs controls: 23.6 ± 1.4 grams) despite similar food intake. Compared to controls, urinary angiotensinogen, total prorenin/renin and sPRR levels were increased in STZ injected mice; these increases were proportionally greater than the trend in increased urinary microalbumin excretion (Table 1). In particular, urinary sPRR excretion was markedly increased in STZ injected mice compared to controls. In a separate experiment, 10 week old male Akita mice bearing a mutated Ins2 gene, demonstrated a 4.8 fold increase in renal medullary renin mRNA expression and a 1.5-fold increase in renal medullary PRR expression. Taken together, these results demonstrate early activation of the intra-renal RAS in Type 1 diabetes. These changes occur independent of the systemic RAS.