Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury

109

AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-induced epithelial secretion of profibrotic factors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFbdependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wnt1 expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptor b-positive myofibroblasts isolated from these kidneys exhibited increased canonical Wnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelialderived Wnt ligand is sufficient to drive interstitial fibrosis provides strong support for the maladaptive repair hypothesis in the AKI to CKD transition.

Section: Discussionmentioning

confidence: 81%

Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk

Maarouf

Aravamudhan

Rangarajan

et al. 2016

109

“…Due to the inconsistent reports about depleting macrophages to establish a role in kidney fibrosis, 29,30 we investigated the gene signature of the Ly6C low population. One key piece of evidence supporting a role in fibrosis is the common gene signature identified between the Ly6C low population and numerous genomic studies linked to fibrotic diseases including kidney transplant patients that have interstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic Analysis Identifies a Unique Gene Signature for Each Macrophage Population As there are conflicting reports on the role of macrophages in fibrosis based on studies with liposome clodronate 29 and the c-fms inhibitor, 30 a genomic approach was taken. Single-cell suspensions of kidney homogenates were flow-sorted based on CD11b/Ly6C expression to isolate each population followed by whole genome array.…”

Section: In Vivomentioning

confidence: 99%

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Clements¹,

Gershenovich²,

Chaber³

et al. 2016

Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemiareperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b + cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis.

“…19,20 This macrophage phenotype not only supports the resolution of postischemic renal inflammation but also actively promotes healing (i.e., tubular repair). [21][22][23] In fact, regenerative tubular epithelial cell proliferation starts as early as 3 hours after tubular injury; however, the resolution of renal inflammation seems to be mandatory to shift the balance of tubular repair and ongoing injury toward structural and functional tubular recovery, [24][25][26] similar to wound healing in general. 27 Therefore, factors that regulate macrophage phenotypes might determine AKI recovery and long-term outcomes.…”

mentioning

confidence: 99%

Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

Lech¹,

Gröbmayr²,

Ryu³

et al. 2014

179

148

The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M 2/2 kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-a blockade with etanercept partially prevented renal atrophy in IRAK-M 2/2 mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage-and TNF-a-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.