Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor

Abstract

Type I human diabetics and streptozotocin-induced diabetic mice with higher genetically determined levels of angiotensin-converting enzyme have an increased risk of developing nephropathy. However, previous experiments in mice and computer simulations indicate that modest increases in angiotensin-converting enzyme have minimal effects on blood pressure and angiotensin II levels, although bradykinin decreases significantly, inferring that bradykinin is critical for protecting the kidney in diabetics. Here, we confirm this inference by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor develop overt albuminuria, excreting the equivalent of >550 mg/day albumin in humans, which contrasts with the microalbuminuria (equivalent to <150 mg/day) seen in their simply diabetic littermates. The overt albuminuria is accompanied by a marked increase in glomerular mesangial sclerosis. The importance of bradykinin demonstrated here bears strongly on how current drugs reduce diabetic nephropathy and suggests that B2 receptor-specific agonists merit consideration in this context.

Fig. 1.

Daily urinary albumin excretion in 6-month-old male mice. Genotypes are wild type at both the insulin 2 and the bradykinin B2 loci (WT = Ins2^+/+, Bdkrb2 ^+/+); wild type for insulin and homozygous null for the B2 receptor (B2^-/- = Ins2^+/+, Bdkrb2^-/-); heterozygous Akita for insulin and wild type for the B2 receptor (Akita = Ins2^+/C96Y, Bdkrb2^+/+); and doubly mutant (Double = Ins2^+/C96Y, Bdkrb2^-/-). P = 0.04, 0.0005, and <0.0001 for wild type versus B2 null, Akita diabetic, and double mutant mice, respectively. P = 0.0003 and <0.0001 for B2 null versus Akita diabetic and double mutant mice, respectively. P = 0.004 for Akita diabetic versus double mutant mice.

Fig. 2.

Photomicrographs of the kidneys with the same four genotypes as shown in Fig. 1. (A) Masson's trichrome staining of renal cortex. (Original magnification, ×40.) (B) Periodic acid-Schiff staining of glomeruli counterstained with hematoxylin. (Original magnification, ×400.)

Fig. 3.

Electron micrographs of kidneys with the same four genotypes as shown in Fig. 1. (Original magnification, ×5,000.)