Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA249

Poster Communications

Mice with reduced intrarenal angiotensin I-converting enzyme are protected against experimentally induced chronic kidney damage

A. Juretzko1, A. Steinbach1, U. Lendeckel2, B. Miehe3, S. Stracke4, R. Rettig1

1. Physiology, University of Greifswald, Karlsburg, Germany. 2. Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany. 3. Anatomy and Cell Biology, University of Greifswald, Greifswald, Germany. 4. Internal Medicine A, University of Greifswald, Greifswald, Germany.


Problem statement: Mice (C57BL/6J-tm(ACE3/3) = ACE-/-) with reduced intrarenal angiotensin I-converting enzyme (ACE) are protected against angiotensin (ANG) II-induced arterial hypertension. The underlying mechanisms are currently not well understood. As it is known, that the renal renin-angiotensin system (RAS) is involved in the development of chronic kidney damage, we investigated whether ACE-/- mice, that have reduced intrarenal ACE but increased intrarenal abundance of ACE2 protein, are protected against experimentally induced chronic kidney damage and whether they show alterations in the renal RAS. Methods: Chronic kidney damage was induced using aristolochic acid I (AAI, 3 mg/kg body weight, i.p., every three days for six weeks followed by six weeks without treatment). At the end of the protocol, animals were anaesthetised with ketamine/xylazine (12,5 mg/ml/2,5 mg/ml, i.p.), the glomerular filtration rate (GFR) was determined using inulin clearance und the kidneys were removed. During the protocol for GFR, ketamine was supplemented as needed. The renal protein abundances of renin, angiotensinogen (AGT), ACE or ACE2 were determined in ACE-/- and C57BL/6J control mice by Western blot analyses. Abundances of specific protein species were determined relative to total protein abundance or GAPDH and normalized to controls. Results: GFR was similar in vehicle-treated mice of both strains. Treatment with AAI significantly decreased GFR in controls but not in ACE-/- mice. ACE-/- mice had 78% lower intrarenal ACE protein abundance than controls and AAI decreased intrarenal ACE protein abundance in both strains. Furthermore, ACE-/- mice had significantly higher intrarenal ACE2 protein abundance than controls and AAI decreased intrarenal ACE2 protein abundance in both strains. Intrarenal AGT and renin protein abundances were similar in both strains. AAI increased intrarenal AGT and renin protein abundances in ACE-/- mice but not in controls. Conclusions: Mice with reduced intrarenal ACE are protected against experimentally induced chronic kidney damage. It remains to be determined whether the increased intrarenal ACE2 protein abundance helps to protect the ACE-/- mice from chronic kidney damage by activating the ACE2/Ang(1-7)/MasR axis.

Where applicable, experiments conform with Society ethical requirements