V. Voronova,1 T. Karelina,1 O. Demin,1 D. Chen2; 1Institute for Systems Biology SPb, Moscow, Russian Federation, 2Pfizer Inc., Cambridge, MA
BACKGROUND: Angiotensin receptor blockers (ARB) are widely used for diabetic kidney disease (DKD) treatment, retarding GFR decrease and leading to slower renal function loss although single ARB administration can cause GFR decrease. The aim of this work was to explore mechanisms of GFR change after single ARB dose.
METHODS: The proposed model describes change of MAP (mean arterial pressure), GP (glomerular pressure), RVR (renal vascular resistance), Kef (ultrafiltration coefficient), RPF (renal plasma flow) and GFR in response to ARB intake, taking into account direct effect of ARB on RVR and Kef (mediated via its binding with receptors in kidneys) and indirect (mediated via systemic pressure changes). Parameters of the model were taken from the literature or fitted against published data.
RESULTS: The final model adequately describes published data on MAP, GFR and RPF response to ARB (Irbesartan, Valsartan) intake and AT II infusion. Simulations of partial contributions of local and systemic mechanisms into GFR response to ARB (Figure) have shown that local effect of ARB on RVR and Kef promotes GFR increase whereas systemic hypotensive effect of ARB causes GFR decrease.
CONCLUSION: GFR decrease in response to ARB intake is reflecting the balance between system and local effect of drugs and is not related to pathological renal function change.