Abstract

Diabetic kidney disease (DKD) is a critical complication associated with diabetes; however, there are only a few animal models that can be used to explore its pathogenesis. In the present study, we established a mouse model of DKD using a technique based on the Developmental Origins of Health and Disease theory, i.e., by manipulating the embryonic environment, and investigated whether a dietary intervention could ameliorate the model’s pathology. Two-cell embryos were cultured in vitro in α-minimum essential medium (MEM; MEM mice) or in standard potassium simplex-optimized medium (KSOM) as controls (KSOM mice) for 48 h, and the embryos were reintroduced into the mothers. The MEM and KSOM mice born were fed a high-fat, high-sugar diet for 58 days after they were 8 weeks old. Subsequently, half of the MEM mice and all KSOM mice were fed a diet containing rice powder (control diet), and the remaining MEM mice were fed a diet containing barley powder (barley diet) for 10 weeks. Glomerulosclerosis and pancreatic exhaustion were observed in MEM mice, but not in control KSOM mice. Renal arteriolar changes, including intimal thickening and increase in the rate of hyalinosis, were more pronounced in MEM mice fed a control diet than in KSOM mice. Immunostaining showed the higher expression of transforming growth factor beta (TGFB) in the proximal/distal renal tubules of MEM mice fed a control diet than in those of KSOM mice. Pathologies, such as glomerulosclerosis, renal arteriolar changes, and higher TGFB expression, were ameliorated by barley diet intake in MEM mice. These findings suggested that the MEM mouse is an effective DKD animal model that shows glomerulosclerosis and renal arteriolar changes, and barley intake can improve these pathologies in MEM mice.

Highlights

  • Type 2 diabetes mellitus (T2DM) is a major cause of chronic kidney disease [1, 2], commonly known as diabetic kidney disease (DKD)

  • We provided first evidence that MEM mice developed from two-cell-stage embryos cultured in vitro in a-minimal essential medium (aMEM) exhibited pancreatic exhaustion and glomerulosclerosis, in contrast to control mice developed from embryos cultured in normal potassium simplex-optimized medium (KSOM)

  • We observed a higher incidence of typical DKD pathology— nodular lesions and glomerular hypertrophy—in MEM mice that were fed a rice-based diet than in control KSOM mice

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Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a major cause of chronic kidney disease [1, 2], commonly known as diabetic kidney disease (DKD). DKD generally develops and progresses with renal glomerular hyperfiltration, microalbuminuria, apparent albuminuria, and low glomerular filtration rate (GFR), and patients eventually require dialysis [3]. A serial, cross-sectional Japanese T2DM cohort study reported that the number of patients with DKD with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 increased from 12.1% in 1996 to 24.0% in 2004 [4]. Glomerular and tubular disorders, induced by mesangial matrix expansion, are considered to be the main features of DKD. Hyperglycemia is known to promote the proliferation of mesangial cells, which leads to the excess production of extracellular matrix (ECM) and induces glomerulosclerosis [5, 6]. Hyperglycemia induces the migration of pericytes from the peritubular capillaries to the interstitial space, thereby causing arteriolosclerosis [7]. Dietary or drug therapies to prevent or ameliorate DKD are not well developed

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