Renal Injury and Its Mechanisms in Lepr^db/db Mice

  Objective   To study the mechanism of renal injury in Lepr^db/db mice with the leptin receptor homozygous deficiency.

  Methods  Ten male of 28-week-old Lepr^db/+ mice with leptin receptor heterozygous deficiency were selected as control group and ten male Lepr^db/db mice with leptin receptor homozygous deficiency were used in this study. After fasting for 8 hours, the body mass, fasting blood glucose (FBG) and glycosylated hemoglobulin (HbA1c) of the mice were measured. Blood of the mice was obtained from femoral artery before euthanasia. Serum creatinine (CRE), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH) and malonaldehyde (MDA) were detected by corresponding kits, and serum interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA) method. The kidney was taken for pathological observation. The expression levels of nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) in renal were analyzed by Western blotting. The mitochondria of renal was isolated by the corresponding kit. Meanwhile, the expression level of lipoic acid synthase (LIAS) in renal mitochondria was measured by Western blotting.

  Results  The body mass, FPG, HbA1c, CRE and BUN levels of the Lepr^db/db mice were significantly increased in comparison with the Lepr^db/+ mice (P<0.05). Compared with the Lepr^db/+ mice, the Lepr^db/db mice renal exhibited glomerular hypertrophy, thickened basement membrane and capillary wall, the mesangial matrix expansion and mesangial cell hyperplasia. Compared with the Lepr^db/+ mice, the serum level of GSH in the Lepr^db/db mice was decreased significantly (P<0.05). The levels of MDA and concentrations of MCP-1, IL-1β and TNF-α in serum of the Lepr^db/db mice were higher than those of the Lepr^db/+ mice (P<0.05). Compared with the Lepr^db/+ mice, the expression of LIAS and Nrf2 protein in the Lepr^db/db mice renal were decreased (P<0.05), while the expression of NF-κB protein was increased (P<0.05).

  Conclusion  LIAS, Nrf2 and NF-κB might play significant roles through regulation of oxidative stress and inflammation in the renal injury of Lepr^db/db mice.