Tadashi Inagami

Role of the Angiotensin Type 2 Receptor Gene in Congenital Anomalies of the Kidney and Urinary Tract, CAKUT, of Mice and Men

Angiotensin type 2 receptor gene null mutant mice display congenital anomalies of the kidney and urinary tract (CAKUT). Various features of mouse CAKUT impressively mimic human CAKUT. Studies of the human type 2 receptor (AGTR2) gene in two independent cohorts found that a significant association exists between CAKUT and a nucleotide transition within the lariat branchpoint motif of intron 1, which perturbs AGTR2 mRNA splicing efficiency. AGTR2, therefore, has a significant ontogenic role for the kidney and urinary tract system. Studies revealed that the establishment of CAKUT is preceded by delayed apoptosis of undifferentiated mesenchymal cells surrounding the urinary tract during key ontogenic events, from the ureteral budding to the expansive growth of the kidney and ureter.

RENAL ANGIOTENSIN CONVERTING ENZYME PROMOTES RENAL DAMAGE DURING URETERAL OBSTRUCTION

PURPOSE We and others have shown that angiotensin II has a pivotal role in renal damage in various renal injuries. Although most angiotensin II actions are associated with the angiotensin type 1 receptor, there is increasing evidence that the angiotensin type 2 receptor also transduces some important effects of angiotensin II. In this regard we recently observed that mice with genetically engineered disruption of the angiotensin type 2 receptor, termed Agtr2 mutants, are more susceptible to structural renal damage after ureteral obstruction. Recent evidence suggests that a genetically determined increase in angiotensin converting enzyme activity in humans promotes end organ damage. Therefore, we determined whether renal damage in Agtr2 mutants is associated with heightened angiotensin converting enzyme activity. MATERIALS AND METHODS We studied 28 wild type and 19 Agtr2 mutant mice with unilateral ureteral obstruction. Seven days after obstruction was created serum samples were obtained to evaluate angiotensin converting enzyme activity. The obstructed and contralateral kidneys were harvested for histological analysis and determination of renal angiotensin converting enzyme activity by high pressure liquid chromatography. RESULTS Renal angiotensin converting enzyme was uniformly higher than serum angiotensin converting enzyme in normal wild type and Agtr2 mutant mice. However, even at baseline Agtr2 mutant mice had strikingly higher renal angiotensin converting enzyme activity than normal wild type mice (mean plus or minus standard error 1,492+/-83 versus 450+/-60 milliunits per gm. tissue weight, p <0.0005). Histological analysis revealed more extensive parenchymal damage in the obstructed kidneys of mutant mice than in identically treated controls. Notably while unilateral ureteral obstruction decreased renal angiotensin converting enzyme activity in each group, activity remained persistently higher in the Agtr2 mutants than in normal mice (mean 742+/-146 versus 310+/-43 milliunits per gm. tissue weight, p <0.005). CONCLUSIONS We propose that elevated renal angiotensin converting enzyme activity contributes to more severe renal parenchymal damage in ureteral obstruction by promoting the availability of growth factors, such as angiotensin II, or depleting antiproliferation factors, such as bradykinin or nitric oxide. These findings complement previous observations that angiotensin converting enzyme inhibition preserves the renal parenchyma after injury, including obstruction.