Renal TLR7 expression is associated with renal injury in female mouse model of systemic lupus erythematosus

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2022

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Chaudhari, Sarika
D'Souza, Bradley
Morales, Jessica
Shimoura, Caroline
Ma, Rong

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with exaggerated immune activation, autoantibody production, and immune complex formation. SLE patients are predominantly women of reproductive age that often present with end organ damage, specifically in the kidneys, and hypertension. This detrimental sequelae is likely due to deposition of the immune complexes and the resulting inflammation, but the exact mechanisms are unknown. It is known however that immune complexes activate toll like receptors (TLRs) on immune cells and TLR7 particularly is known to promote the pathogenesis of SLE. Therefore, we hypothesized that renal TLR7 impairs renal function and drives renal injury and hypertension in female SLE mice. Double-stranded DNA (dsDNA) autoantibodies, a hallmark of SLE, and albuminuria, a marker of renal injury, were monitored at 30 and 35 weeks of age in female and male SLE (NZBWF1) and control (NZW) mice. Glomerular filtration rate (GFR) was measured by sinistrin clearance and renal TLR7 and tumor necrosis factor (TNF)-α expression were measured via Western blot to assess renal function and renal inflammation at the end of 35 weeks. Mean arterial pressure was measured in conscious mice at 35 weeks of age using indwelling arterial catheters. At 30 weeks, female SLE mice had elevated plasma dsDNA autoantibodies (U/ml) compared to female controls (4.6e5 ± 1.3e5 vs 8.9e4 ± 3.3e4; n=3-5; all p< 0.05), male SLE mice (6.3e4 ± 2.7e4), and male controls (4.8e4 ± 9.3e3). At 30 weeks, 32% (7 out of 22) of female SLE mice had albuminuria versus 5% (1 out of 22) of female controls, 5% (1 out of 20) of male SLE, and no male controls. At 35 weeks, 63% (10 out of 16) of female SLE mice had albuminuria versus 5% (1 out of 22) of female controls, 5% (1 out of 19) of male SLE, and no male controls. GFR (µL/min/100 g body weight) was lower in female SLE mice compared to males at this same time point (865 ± 77 vs. 1066 ±60; p=0.029). Female SLE mice expressed a significantly higher renal cortical expression of TLR7 than both female control (p < 0.001) and male SLE mice (p < 0.001). Renal cortical expression of TNF-α, a downstream effector of TLR7, was increased in female SLE mice when compared to both female control mice (p < 0.001) and male SLE mice (p < 0.001). Both female and male SLE mice were hypertensive at 35 weeks: mean arterial pressure (mmHg) was higher in female SLE than female controls (152 ± 5 vs. 126 ± 3; n=6-8; p=0.003) and in male SLE compared to male controls (152 ± 4 vs. 136 ± 4 mmHg; n=6-11; p=0.041). These data indicate that increased expression of renal TLR7 and TNF-α is associated with renal injury and hypertension in female SLE mice. These data also suggest a potential sex difference in the pathogenesis of SLE in males. Therapeutic strategies targeting the TLR7 molecular pathway should be further investigated in both female and male lupus nephritis.

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