Abstract 381: Upregulation of Tumor Necrosis Factor α-converting Enzyme (TACE) Protein Expression in db/db Mice is Reversed by Rosiglitazone

Abstract

TACE, also known as ADAM17, is involved in the ectodomain shedding of several membrane bound proteins. Angiotensin converting enzyme 2 (ACE2), homologue of angiotensin converting enzyme (ACE), is known to be renoprotective by increasing the degradation of vasoactive peptide Angiotensin II (Ang II) to vasodilator peptide Ang - (1-7). It has been shown before that TACE mediates regulated ectodomain shedding of ACE2. PPARγ agonist, rosiglitazone, is known to impart renoprotection by attenuating albuminuria. However, the exact mechanism of renoprotection is not clear. Our previous results and others showed that renal ACE2 protein expression is increased during early stages of diabetes in db/db mice. We also demonstrated increased urinary ACE2 excretion in db/db mice. The goal of this study is to test the hypothesis that TACE is upregulated in db/db diabetic mice and treatment with rosiglitazone imparts renoprotection by attenuating the shedding of renal ACE2 via downregulating TACE protein expression. Male 6 week db/db mice were fed rosiglitazone (20mg/kg/day) for 10 weeks. Metabolic and urinary parameters were monitored weekly. Kidney lysate and urine was used to perform western blot and ACE2 activity (pmols/h/μg protein) respectively. db/db mice demonstrated glucose intolerance, hyperglycemia (348.2±29.9 mg/dL), and albuminuria (0.3±0.05 mg/day) at a very early age. Chronic rosiglitazone treatment normalized blood glucose levels (142.0±12.2 mg/dL), improved glucose tolerance and decreased albuminuria (0.17±0.03 mg/day) in treated db/db mice. Western blot showed increased renal TACE protein expression of db/db mice compared to controls (p<0.05). Treatment with rosiglitazone significantly decreased renal TACE protein expression in treated db/db mice compared to untreated mice (p<0.05). In addition, db/db mice demonstrated a 7 fold increase in urinary ACE2 activity (15.1±4.5) compared to controls (1.74±0.9). Treatment with rosiglitazone significantly attenuated and normalized ACE2 activity in treated db/db mice (0.1±0.06). In conclusion, TACE is upregulated in db/db mice and normalizing hyperglycemia with rosiglitazone could impart renoprotection by decreasing renal TACE protein expression and shedding of renal ACE2.