Abstract P315: Vascular AT1 Angiotensin Receptors Do Not Contribute to Albuminuria or Hyperfiltration in Diabetes

Blockade of the renin angiotensin system (RAS) reduces albuminuria, attenuates hyperfiltration, and slows the progression of diabetic nephropathy (DN) by preventing vasoconstriction and subsequent increases in glomerular hydrostatic pressure. Since RAS blockade disrupts Ang II signaling in all tissues, the specific contribution of vascular actions of AT1 receptors in DN has been difficult to delineate. Therefore, we generated 129 SvEv mice with cell-specific loss of AT1A from VSMCs (SMKOs) using Cre-loxp . To eliminate AT1R from VSMCs, we crossed the SMKO mice with AT1BR -/- mice, lacking the minor AT1B isoform. To study the impact of vascular AT1R in DN, we crossed the AT1B- null SMKOs with mice having the Ins2 C96Y AKITA mutation, which develop DM1 early. To enhance kidney injury, mice underwent uninephrectomy (UNX) at 11wks. Blood glucose levels were elevated (~500mg/dL) and similar at 10, 16 and 24wks between the two groups. Prior to UNX, albuminuria was similar between Control AKITA and AT1B- null SMKO AKITA (62±10 Control AKITA versus 107±27 μg/24hrs SMKO AKITA, P=NS). Albuminuria increased with age in both Control Akita and AT1B- null SMKO AKITA but without significant differences between the groups at 16wks (307±106 vs 313±117 μg/24hrs; P=NS) or 24wks (494±236 versus 730±217 μg/24hrs; P=NS), despite a trend toward higher albuminuria in AT1B- null SMKO AKITAs. There was no significant difference in GFR (using FITC-inulin) between non-diabetic Control and AT1B- null SMKO (15.6±1.2 vs 14.8±0.8 μl/min/g BW), and hyperfiltration was observed in both Control AKITA (23.7±2.4 μl/min/g BW; P=0.003) and AT1B- null SMKO AKITA mice (20.7±1.7 μl/min/g BW; P=0.01) relative to their non-diabetic comparators. However, there was no significant difference in GFR between ControlAKITA and AT1B- null SMKO AKITA (P=NS). Finally we measured mRNA levels of putative kidney injury markers by RTqPCR and found no differences in levels of Col1A1 , NGAL , or TGFB1 mRNA between Control AKITA and AT1B null SMKO AKITA. Our studies indicate that the absence of vascular AT1R responses is not sufficient to reduce albuminuria and prevent hyperfiltration in a mouse model of DN. This suggests that blockade of AT1R in other cell lineages may contribute to beneficial actions of ARBs in DN.