Abstract 384: Angiotensin II Subtype 2 Receptor-Deficiency is Associated With Increased Morbidity and Mortality in a Mouse Model of Chronic Renal Failure
Background: Angiotensin II, the main effector petptide of the Renin-Angiotensin-System, activates at least two G protein-coupled receptors, the AT1 and AT2 receptor (AT2-R) and plays an important role in the pathogenesis of renal diseases, e. g., chronic renal failure. Renal diseases are in turn often associated with an increased cardiovascular morbidity. Therapeutic concepts to improve renal and cardiovascular outcome of patients with renal diseases mainly concentrate on the AT1 receptor. In this regard, the role of the AT2-R still remains elusive.
Methods: To identify the influence of AT2-R on the development and progression of chronic renal failure, we performed 5/6 nephrectomies in wild-type (WT) and AT2-R knock out (KO) mice, a procedure that induces chronic renal failure in treated mice. Subsequently, we investigated postoperative mortality during a two month observation period. Furthermore, renal damage was assessed histologically and by measuring urinary albumin excretion. Moreover, renal expression of markers of inflammation and fibrosis was analysed using Real Time PCR.
Results: In our model of chronic renal failure we observed a significantly higher mortality rate in KO mice as compared to WT mice (66,7% vs. 28,6% mortality, p=0.008 (Log-Rank-Test); n=21/21). Furthermore, renal damage assessed histologically and by its surrogate albuminuria was significantly higher in KO mice than in WT mice (KO vs. WT (albumin/creatinine): 31±19 vs. 0.7±0.3 μg/mg, p<0.01 (n=16/17); three weeks post-surgical). Higher mortality and renal morbidity in KO mice were not due to differences in post-procedural blood pressure values (KO vs. wild type: 115±17 vs. 116±14 mmHg (n=15/13)) but were associated with a significantly higher expression of MCP-1 and fibronectin mRNA in renal tissue of these animals.
Conclusion: In our model AT2-R deficiency aggravates chronic renal failure in a blood pressure-independent manner. Hence, the AT2-R may represent a new therapeutic target for the treatment of chronic renal diseases.