Autor:innen:
S. Kopf (Heidelberg, DE)
V. Kumar (Heidelberg, DE)
Z. Kender (Heidelberg, DE)
A. Sulaj (Heidelberg, DE)
M. Blume (Weinheim, DE)
E. Kliemank (Heidelberg, DE)
J. Zemva (Heidelberg, DE)
M. Brune (Heidelberg, DE)
K. Shahzad (Leipzig, DE)
B. Isermann (Leipzig, DE)
T. Fleming (Heidelberg, DE)
S. Herzig (München, DE)
J. Szendrödi (Heidelberg, DE)
P. Nawroth (Heidelberg, DE)
Aim: Diabetes-associated complications are related with fibrosis. This study investigated the cascade of increased DNA-damage, senescence and senescence associated phenotype (SASP) in association with progression of fibrosis in experimental diabetes and in participants with type 2 diabetes in a 4-year follow-up study.
Methods: In 4 months db/db-mice and age-matched controls kidney, lung and liver were studied histologically for DNA-damage and fibrosis. At baseline DNA-damage markers in WBC, urinary p21-excretion (senescence marker), IL6 and TGFβ-1 (SASP markers) were measured in 115 controls, 34 pre-diabetes and 221 patients with type 2 diabetes. Albumin-creatinine-ratio was used as marker for nephropathy, restrictive lung pattern for restrictive lung disease (RLD) and increased fibroscan (>7kPa) as indirect evidence for non-alcoholic steatosis hepatis at baseline and during follow-up study.
Results: After 4 months db/db-mice showed increased DNA-damage and fibrosis in kidney, lung, and liver than the controls. At baseline DNA-damage markers, senescence and SASP were significantly increased in patients with diabetes and presence of nephropathy, RLD and increased liver stiffness were significantly associated with this cascade. After 4-years progression of nephropathy was significantly associated with increased DNA-damage, senescence and SASP and progression of RLD was only associated with increased DNA-damage and IL6. However, progression of liver stiffness was not associated with these parameters and HbA1c was not predictive for progression.
Conclusion: In db/db-mice and in a subgroup of patients with type 2 diabetes DNA-damage had an accelerated rate of progression of fibrosis. Thus, the fibrosis could be driven by activated senescence and SASP because of increased DNA-damage.