Abstract 071: CX3CR1 Deficiency Aggravates Renal Damage in Angiotensin II Induced Hypertensive Kidney Injury

Abstract

A dense network of macrophages and dendritic cells (DCs) expressing the chemokine receptor CX3CR1 populates the kidney. We recently reported that CX3CR1 regulates the abundance of DCs selectively in the kidney and promotes renal inflammation in glomerulonephritis. Given that inflammation plays also an important role in hypertensive renal injury, we hypothesized that CX3CR1 deficiency should attenuate renal injury in hypertension by reducing the number of renal DCs.

Renal injury was induced by unilateral nephrectomy, angiotensin II (Ang II) infusion (1.5 ng/min/g) and salt (0.9% drinking water).

Ang II induced heavy proteinuria (measured as albumin/creatinine ratio in mg/mg) compared to controls (0.1±0.0) and proteinuria was unexpectedly more severe in knockout mice than in wildtype (WT) mice (day 3 after of Ang II infusion: 19.2±5.4 vs. 2.5±0.6 p<0.01, day 14: 32.4±8.5 vs. 9.2±2.6 p<0.05 n=13 and 11 respectively). Histologic evaluation of kidney sections revealed also an increased number of proteinaceous casts and more glomerular injury in knockout mice (casts 1.1±0.3 vs. 0.1±0.1/high power field, glomerular injury score 0.95±0.06 vs. 0.57±0.06, p<0.01). Also plasma cholesterol levels were significantly higher in knockout mice than in WT mice (145±11 vs. 105±6 mg/dl, p<0.01). No difference was found for blood pressure and cardiac injury (hypertrophy, fibrosis, fetal gene expression) between both groups. Flow cytometric analysis revealed that Ang II infusion significantly increased the number of renal CD11c⁺/MHCII⁺ DCs in WT (38.5±1.4%, gated on CD45⁺ cells) compared to controls (31.8±3.6%, p<0.05). However, a significant decrease of renal DCs was found in hypertensive CX3CR1 deficient mice (15.2±1.5%, p<0.001). In contrast, the number of CD11b^intermediate/F4/80^high macrophages was 8 times higher in the kidney of CX3CR1 deficient mice compared to wildtype mice (5.5±1.5 vs.0.9±0.2%, p<0.01). These findings show that CX3CR1 deficiency reduces renal DC numbers and increases numbers of renal macrophages in hypertension. Surprisingly, despite reduced DC numbers, CX3CR1 deficiency increases proteinuria and glomerular injury, thus, CX3CR1 inhibition should be avoided in hypertension because it may promote proteinuria and renal injury.