SP024
MURINE RECOMBINANT ACE2 ATTENUATES KIDNEY INJURY IN EXPERIMENTAL ALPORTS SYNDROME (AS)

Introduction and Aims: ACE2 is a monocarboxypeptidase in the renin angiotensin systemthat catalyzes the breakdown of Angiotensin II (AngII) to Ang1-7. We have reported that ACE2 expression and activity in the kidney are reduced in experimental AS but the impact of this finding on kidney disease progression has not been studied. Accordingly, we evaluated the effects of treatment with murine recombinant ACE2 (mrACE2) inCol4A3^-/- mice, a model of AS characterized by proteinuria and progressive renal injury.

Methods: The mrACE2 was administered from 4 -7 weeks of agevia osmotic mini-pump (0.5mg/kg/day).

Results: Treatment with mrACE2 led to an increase in both kidney renal ACE2 expression and the urinary ACE2 excretion rate in 7-week-old Col4A3^-/- mice compared to untreated group. Kidney AngII levels declined and kidney Ang1-7 levels increased. These effects were associated with a significant decrease in proteinuria in the treated 7-week-old Col4A3^-/- mice compared to the untreated group. The inflammatory cytokine IL-6and F4/80, a macrophage marker,werealso reduced by treatment withmrACE2. Transforming growth factor-β1 (TGF-β1),col1α1, and alpha smooth muscle actinlevels were increased in the kidneys of 7-week-old Col4A3^-/- mice and all were reduced by mrACE2.

Conclusions: Treatment with mrACE2 alters angiotensin peptide metabolism in the kidneys of Col4A3^-/- mice and attenuates the progressionof AS nephropathy.We conclude that ACE2 is an important determinant of kidney injury in experimental AS.