How Cellular Crosstalk Is Revolutionizing Our Fight Against Fibrosis
Imagine your body's repair system going haywire—after an injury, instead of healing properly, it creates so much scar tissue that eventually your organs stop functioning.
This isn't science fiction; it's the reality of fibrotic disease, a process responsible for nearly 45% of all deaths in developed countries . At the heart of this problem lies a fascinating cellular drama playing out between three key receptors on the surface of specialized cells called myofibroblasts. Recent groundbreaking research has uncovered that these receptors don't work in isolation but engage in constant molecular crosstalk that either promotes or prevents fibrosis—with major implications for treating both kidney and heart disease.
Fibrosis represents a failed wound-healing response to persistent injury or inflammation. Instead of a neatly repaired tissue, the body deposits excessive extracellular matrix (ECM)—primarily collagen—that accumulates like biological concrete, progressively hardening organs and destroying their function 2 . Whether in the kidneys, heart, lungs, or liver, the outcome is often the same: organ failure and death. Despite its devastating impact, effective anti-fibrotic treatments have remained elusive—until now.
At the center of fibrosis are myofibroblasts—specialized cells that normally play a crucial role in tissue repair. When you're injured, fibroblasts are activated by cytokines like TGF-β1 and transform into myofibroblasts, which produce ECM proteins to provide structural integrity during healing . In healthy repair, once the wound is closed, the myofibroblasts disappear. However, under conditions of chronic injury or inflammation, these cells persist, becoming the primary drivers of pathological scarring 2 .
"The ECM, composed of proteins such as collagen and fibronectin, is normally degraded by metalloproteases (MMPs) and remodeled to rebuild the parenchymal tissue architecture. However, repeated injury or chronic inflammation does not provide enough time for the ECM to be resolved and the accumulation of ECM can form fibrotic lesions" .
This persistent activation leads to a vicious cycle of scar tissue buildup that gradually compromises organ function.
What makes myofibroblasts so interesting to fibrosis researchers is the trio of receptors they express—each with a distinct role in the scarring process:
The "Good Guy" that often counteracts AT1R. AT2R activation typically produces effects that are protective, anti-inflammatory, and anti-fibrotic 2 . Interestingly, AT2R is poorly expressed in healthy adult tissues but dramatically upregulated after injury.
The "Peacemaker" receptor. When activated by the hormone relaxin (or its recombinant form serelaxin), RXFP1 sets off a cascade of anti-fibrotic signals 1 2 . It inhibits TGF-β1 signaling, reduces collagen production, and increases matrix-degrading MMP activity.
For years, researchers viewed these receptors as operating independently. The groundbreaking discovery that they actually communicate directly with each other has opened new horizons for fibrosis treatment.
The story took an unexpected turn when researchers noticed something puzzling: the anti-fibrotic effects of serelaxin were mysteriously abolished by AT1R blockers—the very drugs prescribed to combat fibrosis by inhibiting the "bad" AT1R receptor 1 2 . This paradox launched an intensive investigation into the hidden relationships between these receptors.
Blocking the "bad" AT1R receptor with ARB drugs unexpectedly reduces the effectiveness of serelaxin's anti-fibrotic action through RXFP1.
This suggests these receptors form a functional complex rather than working independently.
To unravel this mystery, researchers designed a comprehensive study examining the signal transduction mechanisms of serelaxin in both primary rat renal myofibroblasts and human cardiac myofibroblasts in vitro, complemented by three different animal models of fibrosis in vivo 1 2 3 . The experimental approach was multifaceted:
Researchers treated primary myofibroblasts with serelaxin in the presence or absence of specific AT1R blockers (irbesartan and candesartan) and AT2R antagonists (PD123319), then measured downstream anti-fibrotic signaling markers.
Using transfected cell systems, researchers investigated whether serelaxin directly binds to AT1R and whether these receptors physically interact.
| Model Type | Specific Model | Organ Studied | Key Measurements |
|---|---|---|---|
| In Vitro | Primary rat renal myofibroblasts | Kidney | ERK1/2 phosphorylation, cGMP production, Smad2 phosphorylation |
| In Vitro | Human cardiac myofibroblasts | Heart | ERK1/2 phosphorylation, cGMP production, Smad2 phosphorylation |
| In Vivo | Unilateral ureteric obstruction (UUO) | Kidney | Collagen deposition, MMP activity, myofibroblast markers |
| In Vivo | Isoprenaline-induced cardiomyopathy | Heart | Left ventricular fibrosis, collagen content, cardiac function |
| In Vivo | High-salt diet | Kidney & Heart | Blood pressure, organ damage, collagen accumulation |
The findings challenged conventional wisdom about how these receptors function. While researchers confirmed that serelaxin does not directly bind to AT1R, they made the crucial discovery that constitutive AT1R-RXFP1 interactions could form—meaning these receptors physically associate with each other even without activation 1 2 .
This physical interaction explained why AT1R blockers could interfere with RXFP1 signaling even though they target different receptors.
The most striking result was that both irbesartan and candesartan—commonly prescribed ARB medications—abrogated the anti-fibrotic signal transduction of serelaxin in both kidney and heart myofibroblasts 1 2 4 . This effect wasn't limited to cell cultures; in animal models, candesartan also blocked serelaxin's ability to reduce fibrosis in the left ventricle of mice with cardiomyopathy.
Further experiments revealed that renal and cardiac myofibroblasts express all three receptors (AT1R, AT2R, and RXFP1) and that antagonists acting at any of the three receptors could directly or allosterically block the anti-fibrotic effects of either serelaxin or an AT2R agonist (compound 21) 1 2 . This triangular relationship suggests these receptors function as an integrated signaling complex rather than as independent entities.
| Experimental Setting | Effect on Anti-fibrotic Signaling |
|---|---|
| Serelaxin alone | Strong anti-fibrotic signaling |
| Serelaxin + AT1R blocker | Abrogated anti-fibrotic effects |
| Serelaxin + AT2R antagonist | Reduced anti-fibrotic effects |
This discovery explains the paradoxical finding that blocking the "bad" AT1R receptor can interfere with the anti-fibrotic effects of serelaxin, suggesting these receptors work as an integrated complex.
These findings have profound implications for how we treat fibrotic diseases. The discovery of functional crosstalk between AT1R, AT2R, and RXFP1 explains why some drug combinations may be less effective than expected and points toward more strategic therapeutic approaches.
Millions of patients with kidney and heart conditions currently take ARBs (AT1R blockers) like irbesartan and candesartan to slow disease progression. While these drugs provide benefit by blocking the pro-fibrotic effects of AT1R, the new research suggests they might inadvertently undermine the body's natural anti-fibrotic mechanisms mediated by relaxin/RXFP1 signaling 1 2 .
This doesn't mean patients should stop these medications—they remain valuable—but it highlights the need for more sophisticated treatment strategies.
Similarly, drug developers working on serelaxin or AT2R agonists as potential anti-fibrotic therapies must consider these receptor interactions when designing clinical trials. The effectiveness of these emerging treatments likely depends on the specific combination and timing of administration relative to standard ARB therapy 1 .
Rather than giving drugs simultaneously, might staggered administration preserve the benefits of both ARBs and RXFP1/AT2R activators?
Could we develop drugs that block the pro-fibrotic actions of AT1R without disrupting its beneficial interactions with RXFP1?
The ideal approach might involve carefully calibrated combinations that modulate all three receptors in a balanced manner.
The receptor complexes themselves could be targeted, potentially with molecules that stabilize them in specific configurations that favor anti-fibrotic signaling.
Stagger administration of ARBs and RXFP1 agonists to avoid interference
Develop AT1R blockers that don't disrupt RXFP1 signaling
Precisely balanced multi-receptor targeting
Molecules that lock receptors in anti-fibrotic configurations
Studying these complex receptor interactions requires sophisticated tools and techniques. Here are some of the key reagents and methods that enabled these discoveries:
| Research Tool | Specific Examples | Application in Fibrosis Research |
|---|---|---|
| Receptor Agonists | Serelaxin (RLX), Compound 21 (C21) | Activate RXFP1 and AT2R receptors to study anti-fibrotic effects |
| Receptor Antagonists | Irbesartan, candesartan, PD123319 | Block specific receptors to elucidate their roles in signaling pathways |
| Cell Models | Primary renal/cardiac myofibroblasts, transfected cell lines | Study receptor function in relevant cell types |
| Animal Models | UUO, isoprenaline-induced cardiomyopathy, high-salt diet | Investigate fibrosis in whole-organ systems |
| Signaling Assays | AlphaScreen™ SureFire pERK, HTRF™ cGMP | Measure key downstream signaling molecules |
| Fibrosis Readouts | Collagen deposition, MMP activity, α-SMA expression | Quantify extent of fibrosis and treatment effects |
Unilateral ureteric obstruction to induce renal fibrosis
Repeated isoprenaline administration to induce cardiac fibrosis
Hypertension-induced fibrosis in kidney and heart
The discovery of functional crosstalk between AT1R, AT2R, and RXFP1 represents a paradigm shift in how we understand and treat fibrotic diseases. Rather than viewing each receptor in isolation, we now recognize they form an integrated signaling network that collectively determines whether healing follows a healthy or fibrotic path.
As research advances, we're moving closer to therapies that can precisely modulate this receptor triangle to promote healing while preventing excessive scarring. The goal is no longer simply to block "bad" receptors or activate "good" ones, but to orchestrate their interactions in a way that restores the body's natural balance between tissue repair and regression.
The future of fibrosis treatment lies in understanding and manipulating the complex crosstalk between AT1R, AT2R, and RXFP1 receptors rather than targeting them individually.
While challenges remain, these insights offer hope for the millions affected by fibrotic diseases. By decoding the molecular conversations between cells, we're developing the knowledge needed to intervene more intelligently in the scarring process—potentially turning fatal conditions into manageable ones and preserving organ function for longer, healthier lives.
The complex dance of receptors within our cells continues to reveal its secrets, reminding us that in biology, as in life, communication is everything.
Identification of receptor crosstalk paradox
Elucidation of physical interactions between receptors
Design of drugs that modulate receptor complexes
Testing new strategies in human trials