# Macrophage Plasticity and Regulatory Networks During the Transition from Inflammation to Fibrosis in the Kidney

## TL;DR

This paper reviews how macrophages change during kidney inflammation and fibrosis, and how these changes contribute to chronic kidney disease.

## Contribution

The paper provides a comprehensive overview of macrophage plasticity and regulatory networks in kidney fibrosis.

## Key findings

- Macrophages transition between pro-inflammatory and pro-fibrotic states during kidney injury and fibrosis.
- Chemokine–receptor networks and mechanosensitive ion channels mediate macrophage recruitment and proliferation.
- Metabolic reprogramming and epigenetic modulators stabilize the fibrotic macrophage phenotype.

## Abstract

Kidney fibrosis represents the final common pathway of nearly all progressive renal diseases, linking acute kidney injury (AKI) and chronic kidney disease (CKD) through a maladaptive repair process. Regardless of etiology, persistent inflammation and excessive extracellular matrix (ECM) deposition drive irreversible structural distortion and functional decline in the kidney. Among cellular mediators, macrophages occupy a central role across the continuum from acute injury to fibrosis, orchestrating both tissue injury and repair through dynamic transitions between pro-inflammatory (M1) and pro-fibrotic (M2) states in response to local cues. Here, we synthesize macrophage-driven mechanisms of renal fibrosis, emphasizing recruitment, infiltration, and local proliferation mediated by chemokine–receptor networks and mechanosensitive ion channels. In addition, in this review paper, we provide an overview on the dual roles of macrophages in acute inflammation and chronic remodeling through key cytokine signaling pathways (TLR4/NF-κB, IL-4/STAT6, TGF-β/Smad, IL-10/STAT3), highlighting how metabolic reprogramming, mechanochemical feedback via Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling, and epigenetic modulators collectively stabilize the fibrotic macrophage phenotype. Also, emerging insights into mitochondrial dysfunction, succinate–succinate receptor 1 (SUCNR1) signaling, and autophagy dysregulation reveal the metabolic basis of macrophage persistence in fibrotic kidneys. Understanding these multilayered regulatory circuits offers a framework for therapeutic strategies that selectively target macrophage-dependent fibrogenesis to halt the transition from acute injury to chronic renal failure.