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Diabetic Nephropathy Accelerated by Imbalance of Renal Renin‐Angiotensin System Components in db/db Mice with High Fat Diet
Author(s) -
Wang GuanHua,
Cho ChingChang,
Lin ChungI,
Wu HsiTien,
Lin ChihSheng
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.780.6
Subject(s) - medicine , endocrinology , diabetic nephropathy , creatinine , nephropathy , insulin resistance , blood urea nitrogen , candesartan , diabetes mellitus , kidney , angiotensin ii , type 2 diabetes , adipose tissue , blood pressure
Fat accumulation is associated with insulin resistance that results from overactivation of angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 receptor (AT1R) axis of renin‐angiotensin system (RAS). Ang II induces macrophage infiltration into adipose tissue and increases pro‐inflammatory cytokines (TNF‐alpha and IL‐6) to inhibit insulin receptor that causes insulin resistance and hyperglycemia. Several studies support antihypertensive efficacy of RAS blockade in the patients with type 2 diabetes and obesity. Future studies should address the role of kidney‐specific deficiency of RAS components to definitively determine the relevance of renal RAS to the disease progression related with diabetic or obesity‐related nephropathy. Due to BKS db/db mice is similar in human type 2 diabetes which can be spontaneously induced diabetic nephropathy. Therefore, male BKS db/db mice were fed a high‐fat diet (HFD; 60% of fat in diet) from 8 to 12 weeks of age and fed a normal diet (ND) from 8 to (12 or 20) weeks of age then the animals were sacrificed for the further assays in this study. The changes of serum and urine biochemistry, renal MAPK and STAT3 signaling pathways, RAS components, and pathology associated with diabetic nephropathy were evaluated in these mice. According to the results of body and kidney weight, serum (triglycerides, total cholesterol, glucose, creatinine, blood urea nitrogen, and albumin) and urine (creatinine, blood urea nitrogen, and albumin) biochemical assays, our data confirm the previous reports that db/db mice can be spontaneously induced hyperglycemia at 8 week of age and progressive nephropathy at age of approximate 20 weeks in the mice fed with ND. However, nephropathy and severe diabetic dyslipidemia was occurred early at age of 12 weeks in the db/db mice fed with HFD. Increasing expression levels of renal ACE and chymase would synergistically generate more Ang II and then abnormally flare‐up ACE/AT1R axis that leads local inflammation and promote the progression of nephropathy. Vascular remodeling via MAPK signaling factor, p‐MEK and p‐ERK1/2, an inflammatory signaling factor, p‐STAT3, in the kidney of HFD‐fed db/db mice were significantly higher than those in the ND‐fed db/db mice. The pathological changes also show that diffuse glomerulosclerosis and mesangial matrix fraction in the kidney tissue of HFD‐fed db/db mice were more serious than those in the db/db mice with ND. In conclusion, HFD treatment accelerate impaired kidney function and progressive diabetic nephropathy by increasing renal ACE and chymase activity of RAS in the db/db mice.