Introduction to Fibroblast Growth Factors in Kidney Biology

The Fibroblast Growth Factor (FGF) family comprises 22 signaling proteins that coordinate essential cellular processes such as proliferation, differentiation, migration, and survival. In the kidney, these factors are indispensable during development, contribute to maintaining tissue homeostasis in adulthood, and become prominently re-expressed following injury to drive regenerative responses. Four high-affinity tyrosine kinase receptors (FGFR1–4) mediate FGF signaling, with heparan sulfate proteoglycans acting as co-receptors to stabilize ligand-receptor complexes and control signal duration. Given the substantial global burden of acute kidney injury (AKI) and chronic kidney disease (CKD), understanding how individual FGFs orchestrate renal repair carries considerable potential for developing new therapies. This authoritative overview examines FGF biology in kidney repair, starting from developmental foundations and progressing through molecular mechanisms to emerging clinical strategies.

The FGF-FGFR Signaling System: Molecular Architecture and Regulation

FGFs initiate signaling by binding to FGFRs, which induces receptor dimerization and transphosphorylation of specific intracellular tyrosine residues. This event recruits adaptor proteins such as FRS2 and GRB2, which activate downstream cascades including the RAS-MAPK, PI3K-AKT, and PLCγ pathways. The resulting biological outcomes, whether proliferation, differentiation, migration, or survival, depend on the identity of the FGF ligand, the FGFR subtype present on the target cell, and the composition of the extracellular microenvironment. Heparan sulfate proteoglycans (HSPGs) serve as critical modulators by binding both FGFs and FGFRs, thereby prolonging signaling duration and preventing uncontrolled diffusion of these potent molecules. This multilayered regulation ensures that FGF signals are tightly controlled in both space and time, a property particularly important during tissue repair when pro-regenerative and anti-fibrotic signals must be carefully balanced.

Structural Features of FGF Ligands and Receptors

The 22 human FGFs range from 155 to 307 amino acids in length and share a conserved core of 120 amino acids that forms a β-trefoil fold. This structural motif is essential for binding to both FGFRs and HSPGs. The four FGFRs (FGFR1–4) are single-pass transmembrane receptors with three immunoglobulin-like domains (IgI–III) in their extracellular region. Alternative splicing of FGFR1–3 at the IgIII domain produces 'b' and 'c' isoforms that exhibit distinct ligand-binding specificities. The IgI domain and the acid box region between IgI and IgII regulate receptor autoinhibition, ensuring that FGF signaling occurs only when appropriate ligands are present.

FGF Subfamilies and Receptor Specificity

The 22 human FGFs are grouped into seven subfamilies based on sequence homology and receptor binding preferences. The FGF1 subfamily (FGF1 and FGF2) binds all FGFR isoforms promiscuously, whereas the FGF7 subfamily (FGF7, FGF10, FGF22) shows high specificity for FGFR2b. The endocrine FGF subfamily (FGF19, FGF21, FGF23) requires the co-receptor Klotho for high-affinity binding, allowing these factors to function in an endocrine manner. This diversity permits FGFs to operate in autocrine, paracrine, and endocrine modes, each suited to different physiological contexts.

FGFs in Kidney Development: Programs Recapitulated in Repair

The mammalian kidney develops from the intermediate mesoderm through reciprocal inductive interactions between the ureteric bud and the metanephric mesenchyme. Multiple FGFs are expressed during nephrogenesis with highly specific spatiotemporal patterns. FGF1 and FGF2 are abundant in the metanephric mesenchyme and promote ureteric bud branching morphogenesis. FGF7 supports collecting duct epithelial cell proliferation through its specific receptor FGFR2b. FGF8 is expressed at the tips of the ureteric bud and is required for nephron patterning, while FGF9 and FGF10 contribute to stromal maintenance and capsular development. Disruption of FGF signaling during development leads to severe renal defects, including renal agenesis or hypoplasia, confirming nonredundant roles for these factors. Importantly, many FGF ligands and receptors that are critical during development become re-expressed in the adult kidney after injury, suggesting that repair mechanisms partially recapitulate developmental programs. This concept has driven substantial efforts to identify FGFs that can restore functional nephrons after damage.

Epigenetic Regulation of FGF Expression During Development

Recent studies have revealed that the developmental expression of FGFs is controlled by epigenetic mechanisms, including DNA methylation and histone modifications. For example, the Fgf2 promoter undergoes demethylation in response to retinoic acid signaling, allowing its expression during early nephrogenesis. Similarly, the Fgf8 locus is regulated by H3K4me3 marks that are established by the MLL3/4 methyltransferase complexes. These epigenetic controls ensure that FGF expression is activated at the right time and place during kidney development. Understanding these regulatory layers has implications for designing therapies that reactivate specific FGF signals during repair without causing uncontrolled growth.

FGFs in Acute Kidney Injury: Orchestrating Tubular Repair

Acute kidney injury (AKI) is characterized by rapid loss of renal function resulting from tubular epithelial cell death, inflammation, and microvascular damage. Following ischemic or nephrotoxic injury, several FGF ligands and their receptors are sharply upregulated. FGF2 is produced by endothelial cells and infiltrating macrophages; binding to FGFR1 on tubular cells promotes proliferation and inhibits apoptosis. FGF7 acts as a potent mitogen for proximal tubule cells by activating FGFR2b and subsequent MAPK signaling, thereby accelerating epithelial repopulation. FGF9 and FGF20 enhance tubular regeneration by activating Wnt/β-catenin signaling, which supports the dedifferentiation and proliferation of surviving tubular epithelial cells. In addition to direct effects on epithelial cells, FGFs modulate the inflammatory response. FGF7 reduces chemokine expression, while FGF2 influences neutrophil and macrophage recruitment, shifting the balance toward tissue repair rather than fibrotic scarring.

Angiogenic Roles of FGFs After AKI

Restoration of the peritubular capillary network is essential for long-term recovery from AKI. FGF2 is among the most potent pro-angiogenic factors known; it stimulates endothelial cell proliferation, migration, and tube formation both in vitro and in vivo. Exogenous FGF2 has been shown to increase peritubular capillary density and improve renal function in preclinical models of AKI. FGF1 and FGF9 also contribute by activating ERK1/2 and AKT pathways in endothelial cells. Notably, the combination of FGF2 with vascular endothelial growth factor (VEGF) produces synergistic angiogenic effects, suggesting that coordinated growth factor signaling is required for full vascular repair. The interplay between FGFs and other growth factors is an active area of investigation, with implications for designing multi-target regenerative therapies.

Interplay Between FGFs and Other Growth Factors in AKI

During AKI, FGFs do not act in isolation but rather interact with a network of other growth factors and cytokines. For example, FGF2 upregulates hepatocyte growth factor (HGF) expression in mesenchymal cells, and HGF in turn enhances tubular cell proliferation. Conversely, transforming growth factor-β (TGF-β) can suppress FGF7 expression, contributing to impaired repair. The balance between FGF and TGF-β signaling may determine whether the injury response leads to functional recovery or fibrosis. Understanding these interactions is important for developing combination therapies that amplify regenerative signals while inhibiting profibrotic pathways.

FGFs in Chronic Kidney Disease and Fibrosis

Chronic kidney disease is marked by persistent inflammation, tubular atrophy, and the progressive accumulation of extracellular matrix components, leading to fibrosis. Within this context, different FGFs play contrasting roles. FGF23 has received the most clinical attention due to its central role in phosphate homeostasis and its strong association with adverse outcomes in CKD patients. FGF23 is secreted by osteocytes and acts on the kidney via FGFR1/αKlotho complexes to promote phosphaturia. In CKD, FGF23 levels rise dramatically as a compensatory response to hyperphosphatemia, but this elevation is independently linked to left ventricular hypertrophy, vascular calcification, and increased mortality. Moreover, FGF23 can promote renal fibrosis when αKlotho is downregulated, a common feature of advanced CKD. In contrast, other FGFs may protect against fibrotic progression. FGF7 reduces fibrosis in models of unilateral ureteral obstruction by suppressing epithelial-mesenchymal transition and maintaining epithelial integrity. FGF21 attenuates renal fibrosis by activating the Nrf2 antioxidant pathway and inhibiting TGF-β signaling. FGF1 also shows antifibrotic properties in some models, reducing collagen deposition and preserving tubular structure. These dual roles, where some FGFs promote fibrosis while others protect against it, underscore the need for targeted modulation of specific FGF pathways.

FGF23 Beyond Phosphate Homeostasis

Recent research has expanded the understanding of FGF23 beyond its classical role in phosphate and vitamin D metabolism. FGF23 has been implicated in immune modulation, as it can activate neutrophils and promote inflammatory cytokine production in monocytes. Additionally, FGF23 suppresses erythropoiesis by inhibiting erythropoietin production and directly affecting erythroid progenitor cells, contributing to anemia in CKD. In the kidney, FGF23 activates the calcineurin-NFAT signaling pathway in podocytes, leading to foot process effacement and proteinuria. These pleiotropic effects make FGF23 an attractive therapeutic target, although strategies that lower FGF23 must carefully avoid causing hyperphosphatemia.

Key FGFs Involved in Renal Repair: Detailed Profiles

  • FGF1 (Acidic FGF): Binds all FGFRs with high affinity. Promotes epithelial and endothelial cell survival and proliferation. Shown to reduce kidney injury in rodent models of AKI, with potential for clinical translation. FGF1 can also inhibit TGF-β signaling, suggesting antifibrotic effects in CKD.
  • FGF2 (Basic FGF): The most extensively studied pro-angiogenic FGF. Enhances tubular cell proliferation and capillary regeneration, and stimulates stem cell mobilization from bone marrow. However, its short half-life and systemic side effects, including hypotension and potential tumor promotion, limit clinical use.
  • FGF7 (Keratinocyte Growth Factor): Highly specific for FGFR2b. Essential for collecting duct and proximal tubule repair. Palifermin (recombinant FGF7) is approved for oral mucositis and is being investigated for AKI. Selective activation of FGFR2b with engineered FGF7 variants may avoid fibrotic side effects.
  • FGF9: Promotes mesenchymal-epithelial crosstalk and enhances regenerative responses after AKI through Wnt signaling. FGF9 may help restore the nephron progenitor pool and has shown synergy with retinoic acid signaling in promoting nephron formation.
  • FGF10: Supports early nephron progenitor expansion and is believed to be important for restoring the progenitor niche after injury. Less studied than FGF7, but emerging evidence suggests a role in promoting collecting duct repair.
  • FGF21: An endocrine FGF with metabolic and anti-fibrotic properties. Activates AMPK and Nrf2 pathways to reduce oxidative stress in tubular cells. Long-acting analogs are in clinical trials for metabolic diseases and show promise for improving renal biomarkers.
  • FGF23: A dual-role factor: essential for phosphate excretion but promotes cardiac hypertrophy, kidney fibrosis, and anemia when levels are excessively high. Its activity is modulated by αKlotho, which is often downregulated in CKD. Direct FGF23 blockade is being explored as a therapeutic strategy.

Therapeutic Approaches Targeting FGF Signaling in the Kidney

The recognition that FGFs drive regenerative processes has inspired multiple therapeutic strategies. Recombinant FGF proteins have been tested in preclinical and clinical settings. Palifermin (recombinant human FGF7) is approved for oral mucositis and has been evaluated for AKI. In phase I/II trials, palifermin reduced the severity of cisplatin-induced AKI in cancer patients, although concerns about tumor promotion in patients with underlying malignancies necessitate careful patient selection. FGF2 has been administered intravenously or via nanoparticle carriers, but its short half-life and systemic effects such as hypotension limit its use. Gene therapy approaches using adenoviral or adeno-associated viral vectors encoding FGF1 or FGF2 have shown efficacy in animal models but face immunogenicity and safety hurdles. More recently, small molecule FGFR agonists and biased ligands that selectively activate reparative pathways without promoting fibrosis are under development. For example, a non-mitogenic FGF7 variant that selectively activates FGFR2b but not other FGFRs has been shown to reduce injury without stimulating fibrosis. Another approach involves the use of FGF1-loaded hydrogel patches that can be applied directly to the kidney surface, providing localized drug delivery. For FGF21, long-acting analogs such as pegozafermin (LLF580) have shown improvements in hepatic steatosis and renal biomarkers in clinical trials for non-alcoholic steatohepatitis (NASH). The development of FGF21 analogs with improved pharmacokinetic profiles and reduced immunogenicity continues to advance.

Challenges in Translating FGF Therapies to the Clinic

Despite the promise of FGF-based therapies, several obstacles remain. First, FGFs have pleiotropic effects; systemic administration can cause unwanted cell proliferation in the skin, retina, or occult malignancies. Second, the timing of therapy is critical: FGF administration may be beneficial during the early repair phase but harmful during established fibrosis, where it could exacerbate scarring by promoting fibroblast activation. Third, many renal patients have altered FGFR expression or reduced co-receptor availability (e.g., αKlotho downregulation in CKD), which could dampen therapeutic responses. Notably, FGF23 itself becomes pathogenic when Klotho is lost, meaning that its therapeutic blockade requires careful monitoring. Fourth, delivery must be optimized to achieve high local drug concentration in the kidney without off-target toxicity. Efforts to encapsulate FGFs in biocompatible polymers, develop kidney-targeted nanoparticles that recognize the megalin receptor on proximal tubules, or use antibody-drug conjugates to deliver FGFs specifically to injured tubules are ongoing.

Clinical Evidence and Ongoing Studies

Clinical data on FGF-based therapies for kidney repair remain limited but encouraging. A small study of intravenous FGF2 in renal transplant recipients showed improved graft function and reduced ischemia-reperfusion injury. Palifermin was tested in a randomized phase 2 trial (NCT00419601) for cisplatin-induced AKI, indicating a trend toward lower serum creatinine increases and reduced need for dialysis. For FGF21, the phase 2 BALANCE study (NCT03486903) evaluated pegozafermin in patients with NASH and showed improvements in renal biomarkers such as estimated glomerular filtration rate (eGFR) and reduced albuminuria. Additionally, researchers are exploring FGF1-loaded nanoparticles to accelerate recovery in acute tubular necrosis. More robust multicenter trials with longer follow-up and appropriate safety monitoring are needed to confirm efficacy and risk-benefit profiles. For a comprehensive review of FGF signaling in the kidney, see PubMed ID: 28684716. For the role of FGF23 in CKD, refer to PubMed ID: 30843788. Additional insights on the renoprotective effects of FGF21 can be found in this review.

Conclusion and Future Directions

Fibroblast Growth Factors are essential for kidney development, homeostasis, and repair. Their ability to promote tubular cell proliferation, angiogenesis, anti-apoptotic signaling, and controlled inflammation makes them attractive therapeutic targets for both AKI and CKD. However, the dual-edged nature of FGF signaling, which can drive fibrosis or malignancy when dysregulated, demands precision approaches. Future research will focus on identifying the most effective FGF ligands for each injury type, developing selective agonists that avoid adverse effects, and co-targeting downstream pathways to enhance repair while limiting scarring. Advances in drug delivery, such as kidney-targeted nanoparticles or controlled-release hydrogels, may enable localized FGF activity. Additionally, combining FGF-based therapies with other regenerative approaches, such as stem cell therapy or epigenetic modifiers, could provide synergistic benefits. Ultimately, a deeper understanding of the spatiotemporal expression of FGFs and their receptors, combined with innovative biomaterials and selective compounds, will pave the way for safe, regenerative therapies that restore kidney function in millions of patients worldwide.