Establishment of genetically engineered mouse model of exocrine pancreas insufficiency

Background: The Keap1-Nrf2 system is a central regulator of cellular responses for oxidative stress. Its aberrant activation in cancer cells contributes to cell proliferation, survival and resistance to chemotherapy. Depletion of Nrf2 blunted pancreatic carcinogenesis driven by mutant K-ras and p53, but the effect of conditional activation of Nrf2 has not yet been assessed. We performed following experiments to clarify the effects of mutant K-ras/p53 expression and Nrf2 activation.Materials and methods: LSL-Kras G12D, p53 LSL R172H, and Pdx-1-Cre mice were provided by the NCI mouse repository. Mice were crossed to generate following genotypes with Keap1-floxed background; Kras G12D::p53 R172H (KPC), Kras G12D (KC), p53 R172H (PC) and Pdx-1-Cre (C) mice. After birth, body weight of mice was checked weekly. Mice were sacrificed at 90 days unless they reached a humane endpoint earlier. Results: Conditional knockout of Keap1, which results in constitutive accumulation of Nrf2, led to the progressive destruction of pancreatic parenchyma in mutant K-ras expressing mice (KPC and KC). These mice revealed severe weight loss and hypoglycemia compared to PC and C mice. Part of the mice died before 90 days. Histologically, pancreatic parenchyma was substituted to fibrotic tissue. Discussion: This mouse model presents progressive loss of acinar cells, leading to malnutrition. Loss of pancreatic parenchyma completes within 90 days, which is faster than previous models of chronic pancreatitis.