Abstract

We studied the non-obese diabetic (NOD) mice model because it develops autoimmune diabetes that resembles human type 1 diabetes. In diabetic mice, urinary albumin excretion (UAE) was ten-fold increased at an “early stage” of diabetes, and twenty-fold increased at a “later stage” (21 and 40 days, respectively after diabetes diagnosis) as compared to non-obese resistant controls. In NOD Diabetic mice, glomerular enlargement, increased glomerular filtration rate (GFR) and increased blood pressure were observed in the early stage. In the late stage, NOD Diabetic mice developed mesangial expansion and reduced podocyte number. Circulating and urine ACE2 activity were markedly increased both, early and late in Diabetic mice. Insulin administration prevented albuminuria, markedly reduced GFR, blood pressure, and glomerular enlargement in the early stage; and prevented mesangial expansion and the reduced podocyte number in the late stage of diabetes. The increase in serum and urine ACE2 activity was normalized by insulin administration at the early and late stages of diabetes in Diabetic mice. We conclude that the Diabetic mice develops features of early kidney disease, including albuminuria and a marked increase in GFR. ACE2 activity is increased starting at an early stage in both serum and urine. Moreover, these alterations can be completely prevented by the chronic administration of insulin.

Highlights

  • Diabetic nephropathy both in humans and rodent models is characterized by an increased glomerular filtration rate (GFR), albuminuria and renal enlargement [1,2,3,4]

  • In Non-obese diabetic (NOD) diabetic mice treated with insulin (Diabetic+INS), glucose levels were markedly decreased as compared with non-treated diabetic mice

  • This study shows that in the NOD model of type 1 diabetes, there is an increase in GFR and glomerular size early in the course of the disease that mimics the renal hypertrophy and hyperfiltration characteristic of early nephropathy in human type 1 diabetes

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Summary

Introduction

Diabetic nephropathy both in humans and rodent models is characterized by an increased glomerular filtration rate (GFR), albuminuria and renal enlargement [1,2,3,4]. The study of kidney involvement in rodent models of diabetes has relied heavily on inducing diabetes using streptozotocin (STZ), a drug that is nephrotoxic [6]. While this approach provides valuable information to examine the effects of hyperglycemia on the kidney, it is limited by variable responses attributable, in part, to the doses used and the duration of exposure [6]. Previous studies have shown the development of albuminuria in the NOD mice [10,11], there is a paucity of information on GFR, blood pressure and detailed kidney pathology findings in this model that so closely resembles human type 1 diabetes. The effect of chronic insulin administration on the evolution of kidney disease development in NOD diabetic mice has not been well characterized

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