Professor Université de Sherbrooke Sherbrooke, Quebec, Canada
Disclosure(s): I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose
Blinded Abstract:
Background: Evidence has shown that decreased renal function is associated with enhanced interstitial fibrosis in patients with diabetic kidney disease (DKD). We have previously published that MKP-2 expression is reduced in the kidney of diabetic mice and patients. Interestingly, only diabetic mice with MKP-2 deletion presented with tubular fibrosis, a hallmark of DKD.
Objectives: To evaluate the role of MKP-2 in macrophage activation and progression of fibrosis and DKD.
Methods: Control C57BL/6 (MKP-2+/+), systemic deletion (MKP-2-/-) and macrophage (Mo) overexpression of MPK-2 (MKP-2-moTG) were administered a 0.25% enriched adenine diet for 4 weeks to induce kidney fibrosis. Macrophages were isolated from all groups of mice exposed to TNF-alpha (10 ng/mL).
Results: MKP-2+/+ mice administered the adenine diet presented with elevated urinary albumin excretion which was worsened in MKP-2-/- mice. The DKD promoted tubular fibrosis and increased TNF-alpha expression in MKP-2+/+ mice, while MKP-2 deletion exacerbated not only kidney fibrosis and TNF-alpha expression, but also macrophage infiltration and expression/secretion of Saa1. FACS analysis of isolated macrophages from the kidney showed elevated M1 in MPK-2 -/- mice, which was reduced in MPK-2-moTG mice. MPK-2-/- macrophages exposed to 24h of TNF-alpha exhibited elevated expression of JNK, NF-kB and Saa1. On the other hand, MKP-2-moTG decreased Saa1 and favored M2 macrophages. These findings were associated with reduced inflammation, macrophage infiltration and fibrosis.
Conclusions: Loss of MKP-2 expression exacerbates kidney fibrosis, macrophage infiltration and chronic inflammation and renal impairment aiding in the faster progression of DKD characteristics.
