Introduction: Kidney Fibrosis and the Metabolic Connection
Kidney fibrosis, essentially scarring of the kidney tissue, is a common final pathway for various forms of chronic kidney disease (CKD). It involves excessive accumulation of extracellular matrix (ECM), progressively impairing kidney function. Growing evidence points to metabolic reprogramming – changes in how cells produce and use energy – as a key player in fibrosis development. Alterations in succinate metabolism, specifically, have emerged as a significant contributor to this damaging process. Here, we explore the intricate relationship between succinate and kidney fibrosis, examining the underlying mechanisms and promising therapeutic avenues.
Succinate: More Than Just a Metabolic Fuel
Succinate is a crucial intermediate in the tricarboxylic acid (TCA) cycle, the cell's central pathway for energy generation. Think of the TCA cycle as the cell's engine, and succinate as one of its key components. However, succinate also functions as a critical signaling molecule, acting like a molecular messenger. It primarily exerts these effects by binding to a specific cell surface receptor called SUCNR1 (also known as GPR91). When activated, SUCNR1 initiates signaling cascades within the cell that influence vital processes like inflammation, blood vessel formation (angiogenesis), and tissue scarring (fibrosis).
Succinate Build-up: A Driver of Kidney Fibrosis
In kidneys affected by chronic disease, the delicate balance of metabolism can be disrupted. Dysfunctional mitochondria, impaired activity of the enzyme succinate dehydrogenase (SDH, which normally processes succinate), or disruptions in the TCA cycle can lead to an abnormal build-up of succinate within kidney tissues. This accumulation isn't benign; it actively promotes inflammation and fibrosis. Elevated succinate levels trigger the SUCNR1 receptor on various kidney cells, including the crucial tubular epithelial cells and scar-producing fibroblasts, directly contributing to the fibrotic response.
How Excess Succinate Promotes Fibrosis: Key Mechanisms
- SUCNR1 Activation: Succinate binding to SUCNR1 on kidney cells (like tubular cells, fibroblasts) and immune cells triggers pro-inflammatory and pro-fibrotic signaling pathways (e.g., MAPK, NF-κB).
- Hypoxia-Inducible Factor (HIF) Stabilization: Excess succinate inhibits enzymes called prolyl hydroxylases (PHDs). This prevents the breakdown of HIFs, transcription factors that, when stabilized, promote processes contributing to fibrosis, including ECM production and altered cell metabolism.
- Epithelial-Mesenchymal Transition (EMT): Succinate can induce EMT, a process where kidney tubular epithelial cells transform into cells resembling fibroblasts, directly contributing to ECM deposition and scarring.
- Inflammation Amplification: SUCNR1 activation, particularly on immune cells, fuels the inflammatory environment within the kidney, creating conditions that further drive fibrosis.
Therapeutic Potential: Targeting Succinate Pathways
The central role of succinate in driving fibrosis makes its metabolic and signaling pathways attractive therapeutic targets. Researchers are actively exploring several strategies: developing drugs that block the SUCNR1 receptor (antagonists), finding ways to restore normal mitochondrial function and SDH activity, reducing succinate production or transport, and implementing anti-inflammatory approaches targeting succinate-driven inflammation. While promising, further research is essential to fully understand succinate's complex roles and translate these findings into effective therapies to combat kidney fibrosis.