Premium
ACE2 gene therapy decreases fibrosis in the pancreas of high fat diet‐fed mice
Author(s) -
Chodavarapu Harshita,
Chhabra Kavaljit,
Shenoy Vinayak,
Raizada Mohan K,
Yue Xinping,
Lazartigues Eric
Publication year - 2013
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.27.1_supplement.1154.7
Subject(s) - medicine , endocrinology , angiotensin converting enzyme 2 , insulin resistance , pancreas , fibrosis , insulin , diabetes mellitus , renin–angiotensin system , chemistry , saline , blood pressure , covid-19 , disease , infectious disease (medical specialty)
Type 2 diabetes mellitus (T2DM) is characterized by progressive loss of β‐cell function and insulin resistance. High fat diet (HFD) activates the renin‐angiotensin system (RAS) and causes hyperglycemia. RAS over‐activity has been linked to pancreatic fibrosis characterized by excessive deposition of collagen and elevated TGF‐β. We propose that Angiotensin Converting Enzyme 2 (ACE2) improves β‐cell dysfunction by attenuating Angiotensin‐II‐induced pancreatic fibrosis. To test our hypothesis, mice (n=6/group) were fed with HFD or regular diet for 16 weeks. At the 13th week, HFD‐fed mice were treated with Lenti‐mACE2 or Lenti‐GFP (intra‐pancreatic injection, 10^6 TU/ml in 100 μl saline). After 16 weeks on HFD, ACE2 gene therapy prevented the increase in fasting blood glucose levels (HFD‐ACE2: 152 ±9 vs. HFD‐GFP: 194 ±10 mg/dl P<0.05), plasma insulin levels (HFD‐ACE2: 6 ±2 vs. HFD‐GFP: 12 ±1 ng/ml P<0.05), and improved glucose tolerance (HFD‐ACE2: 52037 ±2264 vs. HFD‐GFP: 44702 ±1571 P<0.05). Quantitative RT‐PCR shows that HFD produced a 3‐fold increase in collagen I mRNA in the pancreas. ACE2 treatment significantly reduced mRNA expression of TGF‐β1 (HFD‐ACE2: 0.24 ±0.06 vs. HFD‐GFP: 1.4 ±0.3 P<0.05) and collagen I (HFD‐ACE2: 0.26 ±0.1 vs. HFD‐GFP: 1.6 ±0.09 P<0.001). In conclusion, our data demonstrate that ACE2 gene therapy could have a potential therapeutic value in T2DM by attenuating pancreatic fibrosis.