Autor:innen:
T. Pfeffer (Heidelberg, DE)
P. Kirschner (Heidelberg, DE)
C. Wetzel (Heidelberg, DE)
M. Bartosova (Heidelberg, DE)
T. Poth (Heidelberg, DE)
G. Poschet (Heidelberg, DE)
J. Zemva (Heidelberg, DE)
I. Damgov (Heidelberg, DE)
S. Garbade (Heidelberg, DE)
K. Klingbeil (Heidelberg, DE)
C. Schmitt (Heidelberg, DE)
V. Peters (Heidelberg, DE)
Background:
Exogenous carnosine and anserine mitigate diabetic nephropathy in rodents, whether they exert direct renal or indirect systemic effects is unknown. We studied carnosinase-1 KO (Cndp1-KO) mice with selectively 2-9-fold increased carnosine/anserine concentrations in kidney under diabetic conditions.
Methods:
T1DM was established in Cndp1-KO and B6 WT mice by streptotozin (STZ) on high fat (HFD) and normal diet (ND), respectively. Mice were treated for 32 weeks with insulin; body weight (BW), energy and fluid intake, blood sugar, urinary albumin-creatinine ratio (ACR) were assessed monthly, at sacrifice organs were harvested for histopathology and molecular studies.
Results:
BW, energy/liquid intake, organ weights, glucose homeostasis, insulin-dose/BW and ACR were similar between Cndp1 KO STZ, and STZ+HFD and respective WT mice. Renal carnosine/anserine concentrations were reduced in Cndp1-KO STZ (56/44%) and STZ+HFD (53/21%) mice compared to non-diabetic Cndp1-KO mice; concentrations were increased (360/224%) in HFD and (310/218%) in STZ+HFD versus respective ND Cndp1-KO mice. 4-HNE was reduced in STZ and STZ+HFD Cndp1-KO mice compared to WT (50%, p=0.005 in STZ; 86%, p=0.01 in STZ+HFD). Mesangial expansion was increased in Cndp1-KO and in STZ mice by 20-25% and reduced in STZ+HFD to control level. Renal arteriolar vessel/lumen ratio was unaltered. Survival was significantly improved in STZ-Cndp1-KO vs. WT mice (p=0.03) until week 20; but not thereafter. Interstitial fibrosis was reduced in STZ+HFD Cndp1-KO vs. WT (40%, p=0.01), Tgf-β and pSMAD-2/3 were unchanged.
Conclusion:
Increased renal carnosine/anserine concentrations do not alter systemic glucose homeostasis but reduce renal oxidative stress and transiently improve survival of diabetic mice.