Kidney Week

Abstract: FR-PO967

Reduction of DUSP4 Enhances Macrophage Infiltration and Contribution to Renal Fibrosis

Session Information

• CKD: Pathobiology - I
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Rousseau, Marina, Universite de Sherbrooke, Sherbrooke, Quebec, Canada

Marina Rousseau,

• Geraldes, Pedro Miguel, Universite de Sherbrooke, Sherbrooke, Quebec, Canada

Pedro Miguel Geraldes,

Background

Chronic kidney disease (CKD) affects 15% of the world population and is the leading cause of end-stage kidney disease in which 45% of patients are patients with diabetes. Patients with advanced CKD will eventually need dialysis or renal transplantation. Renal interstitial fibrosis (RIF) is an essential characteristic of CKD and is associated with renal function decline. Although macrophages are known to play a role in the generation of fibrosis, their contribution to RIF is not well elucidated. Our laboratory has previously shown reduced DUSP4 expression in the kidney of diabetic mice and patients, and the deletion of DUSP4 in diabetic mice lead to RIF. Objective: Evaluate the role of DUSP4 in macrophage related RIF generation.

Methods

Mice with (Dusp4^WT) or without DUSP4 (Dusp4^KO) were subjected to toxin- (4 weeks of adenine-rich diet) and obstructive-induced (UUO) RIF. Renal function was evaluated by 24-hour urinary albumin excretion. To evaluate the role of DUSP4 in macrophage infiltration, Dusp4^WT and Dusp4^KO were irradiated and transplanted with the bone marrow of the opposite group (generating WT mice specifically DUSP4 KO in the macrophages (Dusp4^WT/mΦKO) and DUSP4 null mice with regular expression of DUSP4 in the macrophages (Dusp4^KO/mΦWT)).

Results

The adenine diet increased albuminuria in Dusp4^WT mice, phenomenon exacerbated in DUSP4 null mice. Adenine and UUO models were associated with increased RIF (Masson Trichrome), RIF markers (Col1, TGF-β, KIM-1 gene expression), macrophage infiltration (F4/80 immunohistochemistry), inflammation markers (IL-1β, TNF-α and CD206 gene expressions), and myofibroblast deposition (α-SMA immunohistochemistry) in Dusp4^WT mice. DUSP4 deletion worsened the above characteristics as well as aggravated tubular atrophy. Furthermore, macrophage and myofibroblast markers colocalized in the interstitial space of Dusp4^KO mice, suggesting macrophage contribution to RIF. Interestingly, the adenine diet administered to Dusp4^WT/mΦKO mice worsened albuminuria to levels similar to Dusp4^KO mice, while Dusp4^KO/mΦWT albuminuria levels were lower. Likewise, Dusp4^WT/mΦKO exhibited similar amounts of RIF compared to whole-body Dusp4^KO mice while Dusp4^KO/mΦWT exhibited lower levels of RIF compared to whole-body Dusp4^KO mice.

Conclusion

The loss of DUSP4 in macrophages contributes to macrophage infiltration and total RIF in the progression of CKD.

Funding

• Government Support – Non-U.S.