Abstract
Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.
Highlights
IntroductionThe prevalence of Diabetic kidney disease (DKD) has remained fairly stable over the last two decades despite advances in the treatment of hyperglycemia, hypertension, and dyslipidemias, as well as the widespread use of renin–angiotensin–aldosterone system inhibitors [2–4]
Abbreviations 8-OHdG, 8-hydroxy-20-deoxyguanosine; Arg, L-arginine; Asp, L-aspartic acid; BW, body weight; CE-MS, capillary electrophoresis coupled with mass spectrometry; Citrulline, L-citrulline; Diabetic kidney disease (DKD), diabetic kidney disease; eNOS, endothelial nitric oxide synthase; ESL, endothelial surface layer; FBG, fasting blood glucose; FITC, fluorescein isothiocyanate; Glomerular basement membrane (GBM), glomerular basement membrane; GD, glomerular diameter; KK, KK/Ta; KK-Akita, KK/Ta-Ins2Akita; NO, nitric oxide; PAS, periodic acid–Schiff; PLS-DA, projection on latent structure discriminant analysis; VIP, variable importance in the projection; WGA, wheat germ agglutinin
The results indicate that the levels of urea and Citrulline in the DKD group were significantly higher than those in the Control group when these were compared at the same weeks of age
Summary
The prevalence of DKD has remained fairly stable over the last two decades despite advances in the treatment of hyperglycemia, hypertension, and dyslipidemias, as well as the widespread use of renin–angiotensin–aldosterone system inhibitors [2–4] These therapies aim to slow the progression of DKD; eventually. Abbreviations 8-OHdG, 8-hydroxy-20-deoxyguanosine; Arg, L-arginine; Asp, L-aspartic acid; BW, body weight; CE-MS, capillary electrophoresis coupled with mass spectrometry; Citrulline, L-citrulline; DKD, diabetic kidney disease; eNOS, endothelial nitric oxide synthase; ESL, endothelial surface layer; FBG, fasting blood glucose; FITC, fluorescein isothiocyanate; GBM, glomerular basement membrane; GD, glomerular diameter; KK, KK/Ta; KK-Akita, KK/Ta-Ins2Akita; NO, nitric oxide; PAS, periodic acid–Schiff; PLS-DA, projection on latent structure discriminant analysis; VIP, variable importance in the projection; WGA, wheat germ agglutinin.
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