Insulin-like growth factor 2 (IGF2) is a peptide hormone that is important for embryonic development and the regulation of metabolic processes (1,2). IGF2 expression is tightly regulated by genomic imprinting, which ensures spatially and temporally precise activity (3,4). Beyond its role in development, IGF2 is involved in kidney physiology by promoting cell proliferation, metabolic activity and tissue repair (5–7). Emerging evidence implicates IGF2 dysregulation in the pathogenesis of several kidney disorders, including acute kidney injury (AKI) (8), chronic kidney disease (CKD) (9) and renal malignancies (10). Through interactions with receptors such as IGF1 receptor (IGF1R), insulin receptor isoform A (IR-A) and IGF2 receptor (IGF2R), IGF2 activates signaling pathways, including the PI3K/Akt and MAPK pathways, that modulate inflammation, fibrosis and cell survival (11,12) (Fig. 1). The present review summarizes the structural characteristics and biological functions of IGF2, its regulatory mechanisms and its involvement in kidney diseases, highlighting its potential as both a diagnostic biomarker and a therapeutic target.

IGF2, a polypeptide hormone, has a similar action as insulin, yet its biological activity is low (approximately 14% of that of insulin) (13). The IGF2 gene is located on human chromosome 11p15.5 and spans ~30 kb of genomic DNA. It encodes a 7.5-kDa peptide comprising 67 amino acid residues and shares ~67% sequence homology with insulin-like growth factor 1 (IGF1) (14).

IGF2 is widely expressed in embryonic and fetal tissues, although transcript levels vary considerably across different organs (15). The gene is regulated by five distinct promoters (P0-P4) and consists of 10 exons, with only the final three exons encoding protein-coding sequences (15,16). These promoters are differentially regulated in a tissue- and developmental stage-specific manner, giving rise to functionally distinct mRNA isoforms (16,17). Each promoter is functionally active at specific stages of development and in distinct tissue types. For example, the P0 promoter is predominantly active in the placenta and serves a role in determining placental size and composition. Loss of P0 promoter activity reduces passive diffusion across the placenta, resulting in fetal growth retardation, although systemic levels of fetal IGF2 remain unaffected. This observation suggests that placental IGF2 expression operates independently of circulating IGF2 levels (18).

The P1 promoter is primarily active in the adult liver and the choroid plexus of the brain and contains an internal ribosomal entry site (16). P2 is mainly active in the fetal liver, whereas P3 and P4 drive expression in non-hepatic fetal and adult tissues. Notably, P3 and P4 are epigenetically silenced after birth but may be reactivated in certain tumors [including Wilms' tumor (19) and rhabdomyosarcoma] (20,21). Both P3 and P4 contain canonical TATA and CCAAT boxes recognized by RNA polymerase II, while P2 lacks these elements (22). Transient transfection assays have demonstrated that the activity of P2, P3 and P4 varies by cell type and species. For example, P2 is minimally active in most cell lines, whereas P3 exhibits the highest transcriptional activity in hepatocyte-derived human cells (23). Overall, IGF2 transcription declines sharply in most tissues after birth (16).

IGF2 serves an important role in tissue development and growth, particularly during embryogenesis (24). The biological functions of IGF2 are primarily mediated through interactions with three specific receptors: IGF1R, IR-A and IGF2R (11,12). IGF1R is a transmembrane tyrosine kinase receptor structurally related to the insulin receptor (IR) (9,19,25). Upon binding IGF2, IGF1R activates the PI3K/Akt and MAPK signaling cascades, thereby promoting cell proliferation, differentiation and survival, which are processes that are important for embryonic tissue and organ formation (11,26). IGF1R signaling also serves a central role in tumor biology by enhancing cell survival via anti-apoptotic mechanisms, particularly in IGF1R-dependent malignancies (27).

Compared with IGF1R, IR-A has a higher binding affinity for IGF2 and is predominantly expressed in fetal tissues and specific cancer types, including colorectal cancer, osteosarcoma and thyroid cancer (23,28,29). Upon binding to IGF2, IR-A activates the PI3K/Akt and MAPK pathways, regulating cell metabolism, proliferation and survival, and contributing to tumor growth and adaptability (30–32). Under specific pathological conditions, such as tumors that excessively secrete IGF2, notably including mesenchymal tumors and hepatocellular carcinomas, IGF2 can induce hypoglycemia by activating the IR-A signaling pathway. The aforementioned tumor cells commonly highly express IGF2 mRNA (33–35). However, defective post-translational processing leads to the production of a high molecular weight precursor (15–25 kDa), referred to as pro-IGF2 or ‘big IGF2’, characterized by an uncleaved E-domain extension (36–38). Under physiological conditions, mature IGF2 circulates primarily as part of a 150-kDa ternary complex with IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS). This large complex is unable to cross the capillary endothelium, thereby limiting its biological activity (36,38).

By contrast, pro-IGF2 binds to IGFBP-2 or IGFBP-3 to form a smaller (~50 kDa) binary complex. Steric hindrance from the uncleaved E-domain prevents ALS binding, thereby impeding the formation of the ternary complex. Due to its reduced molecular weight, the binary complex can freely diffuse across the capillary endothelium into the interstitial fluid (37). A clinical study demonstrated that serum concentrations of the 50-kDa complex in patients with tumors can be elevated >10-fold compared with normal levels, enhancing its tissue distribution (37). Additionally, pro-IGF2 promotes vascular leakage and tissue penetration by stimulating tumor secretion of VEGF and MMP-9. VEGF increases vascular permeability, while MMP-9 degrades the basement membrane and disrupts endothelial junctions (39,40). Furthermore, tumor-associated neovasculature is often characterized by incomplete basement membranes and loosely connected endothelial cells, creating a ‘leaky’ vascular phenotype that facilitates the extravasation of small molecular complexes (41).

Once within the interstitial fluid, pro-IGF2 retains receptor-binding affinities to both IR and IGF1R similar to mature IGF2 but exhibits 2- to 3-fold greater molar bioactivity, leading to prolonged receptor activation (36,37). Consequently, in patients with extra-pancreatic tumor-induced hypoglycemia, circulating pro-IGF2 levels are markedly elevated and typically normalize following successful tumor resection (42).

The biological effects of ligand binding are notably influenced by receptor subtype. For instance, in 32D clone 3 murine hematopoietic progenitor cells, IGF2 binding to IR-A induces pro-mitotic and anti-apoptotic signaling, whereas its binding to IR-B promotes differentiation (43). In mouse fibroblasts expressing exclusively IR-A, insulin binding elicits metabolic responses (44).

In contrast to IGF1R, IGF2R exhibits distinct structural and functional characteristics and has the highest binding affinity for IGF2. IGF2R is a single-chain transmembrane receptor that lacks intrinsic tyrosine kinase activity and primarily mediates IGF2 degradation via endocytosis, thereby suppressing cellular over-proliferation and reducing tumorigenic potential (45–47). Additionally, IGF2R facilitates lysosomal enzyme trafficking by recognizing mannose-6-phosphate residues and is therefore also referred to as the cation-independent mannose-6-phosphate receptor (46). This function is evolutionarily conserved, and mammalian IGF2R has further acquired the capacity to bind IGF2, thereby enhancing its role in limiting cell proliferation (48). IGF2R also modulates the TGF-β signaling pathway, which is involved in extracellular matrix (ECM) synthesis, immune regulation, and the control of cell proliferation, differentiation and development (49,50). Collectively, these properties allow IGF2R to maintain growth homeostasis under physiological conditions, and inhibit tumorigenesis and progression under pathological conditions (51).

Despite advances in deciphering the complex structure and regulatory mechanisms of IGF2, such as its genomic imprinting and the existence of multiple promoters and isoforms (52,53), the role of IGF2, particularly in renal physiology and pathology, remains to be fully elucidated. The present review focuses on the expression, regulation and function of IGF2 in the kidney, summarizing its contributions to renal development and its involvement in kidney disease.

IGF2 serves a notable role in renal development and the maintenance of kidney function by regulating cellular proliferation, differentiation and metabolic homeostasis (5). IGF2 expression exhibits a distinct spatiotemporal pattern aligned with specific physiological functions across developmental stages (23,54–56).

During embryogenesis, IGF2 is highly expressed and is important for normal renal morphogenesis (57,58). At this stage, IGF2 is primarily secreted by the placenta (6) and exhibits strong expression in renal structures, particularly the ureteric bud and metanephric mesenchyme (7). This elevated expression facilitates nephron formation by promoting the mesenchymal-to-epithelial transition of nephrogenic progenitors, driving the development of renal tubules and glomeruli, and directing mesodermal cell differentiation toward functionally specialized nephron segments (7,24,59). Animal studies have supported the important role of IGF2 during this period: Disruption of IGF2 signaling leads to notably reduced birth weight, whereas overexpression results in accelerated somatic growth (45,60,61). Furthermore, intrauterine growth restriction models have demonstrated that aberrant DNA methylation of the IGF2 promoter reduces its expression, lowers nephron endowment and increases the risk of CKD later in life (7), underscoring the importance of tightly regulated IGF2 expression during renal development.

As renal development reaches completion, IGF2 expression is downregulated (62). In the adult kidney, IGF2 is maintained at basal levels and is primarily localized to vascular structures and interstitial cells surrounding the glomeruli and renal tubules (57,63). IGF2 mRNA exhibits a spatially restricted pattern: It is enriched in the vascular components of the cortex, particularly within the endothelium and adventitia of afferent arterioles, while in the medulla, it is predominantly expressed in vascular and stromal compartments, with negligible expression in tubular epithelial cells (5). This distribution suggests a specialized role for IGF2 in regulating renal vasculature and glomerular function. Basal IGF2 also contributes to renal homeostasis by supporting cellular repair and metabolic balance (63–65). The transition from high embryonic IGF2 expression to adult basal levels appears to be epigenetically regulated, particularly via promoter methylation, ensuring structural and functional stability post-development (8). Notably, a study using IGF1-deficient transgenic mouse models showed that kidney-specific overexpression of IGF2 selectively increased both absolute and relative kidney weight, without altering body weight or the mass of other organs (66). These findings support a unique, organ-specific role for IGF2 in kidney growth, development and homeostatic maintenance, spanning from embryonic morphogenesis to adult physiological function.

The biological effects of IGF2 are primarily mediated via its interaction with IGF1R and IR (67). IGF1R, the primary signaling receptor for IGF2, is widely distributed in the kidney, with prominent expression in renal tubules, glomeruli and mesangial cells (68). The expression of IGF1R is particularly high in proximal and distal tubular segments, underscoring the role of IGF2 in regulating metabolic processes and ion transport in these structures (5). IGF2 promotes the proliferation and differentiation of renal precursor cells predominantly through IGF1R activation, thus contributing to the formation of renal tubules and glomeruli (69). In a mouse model with P2 promoter deletion, resulting in reduced IGF2 expression, pronounced renal abnormalities were observed, manifesting as proteinuria, podocyte depletion, glomerulosclerosis, increased ECM deposition and glomerular basement membrane thickening at 18 months of age (70). These findings emphasize the importance of IGF2 in supporting renal architecture and maintaining nephron functionality, primarily through its role in podocyte health. The observed increase in ECM deposition is a secondary, dysregulated consequence of podocyte injury and loss, manifesting as mesangial expansion and glomerulosclerosis (70). Furthermore, IGF1R activation promotes ECM synthesis in renal tubules, thereby supporting the structural integrity and functionality of renal tissues (71).

IR is another important receptor for IGF2. Although IR primarily regulates glucose metabolism, it is also widely expressed in the kidney (72). In renal tubules and glomerular endothelial cells, IR expression is high and contributes to the regulation of renal blood flow and tubular reabsorption functions (73). Compared with IGF1R, IR displays a more uniform distribution across kidney regions, suggesting a broader role in maintaining renal metabolic homeostasis (74). Additionally, IGF2 may influence ionic transport and water-electrolyte balance in the kidney via IR signaling. An in vitro study has shown that IGF2 expression enhanced sodium uptake in proximal tubular brush border membrane vesicles (65).

Unlike IGF1R and IR, IGF2R lacks intrinsic kinase activity, and is traditionally regarded as a decoy receptor involved in IGF2 internalization and degradation (75). However, a previous study has revealed that IGF2R may serve an active signaling role. IGF2R nuclear translocation has been linked to GSK3, which primes macrophages toward an anti-inflammatory phenotype. These findings reveal a novel immunomodulatory role for IGF2R in macrophages and suggest that IGF2 may influence immune responses within the kidney via IGF2R. Notably, activation of IGF1R, by either IGF1 or IGF2, can antagonize IGF2R signaling, thereby modulating macrophage polarization. The balance between IGF1R and IGF2R activation is important for maintaining macrophage-mediated immune homeostasis and appropriately shaping the immune response to infection or inflammation (76).

Understanding the regulatory mechanisms governing IGF2 expression is important for elucidating its roles in renal development and disease. IGF2 expression is controlled by genomic imprinting, with transcription occurring exclusively from the paternal allele while the maternal allele remains epigenetically silenced (77,78). This monoallelic expression pattern is maintained by DNA methylation at the H19/IGF2 imprinting control region (ICR) and its associated epigenetic regulatory elements (79,80). Specifically, paternal-specific methylation of the ICR, enhancer competition and CCCTC-binding factor-mediated boundary insulation ensure the spatial and temporal precision of IGF2 function during renal development (81).

Loss of genomic imprinting is associated with pathological growth abnormalities. For example, Beckwith-Wiedemann syndrome is caused by IGF2 upregulation and is characterized by somatic overgrowth of the body, including kidney overgrowth (61). Conversely, Silver-Russell syndrome involves IGF2 downregulation and presents with growth restriction of body and the kidneys are generally small in proportion to the overall body growth restriction (82). Experimental models further underscore the important role of imprinting in renal development. These include the model demonstrating that CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus, where it binds the unmethylated imprinting control region (ICR) on the maternal allele to insulate Igf2 from enhancers, thereby silencing it (79), and the model of aberrant establishment of paternal methylation imprint at the H19/Igf2 ICR, which disrupts the parent-of-origin-specific expression pattern (83,84). In both cases, enhancer deletion at the 3′ end of the H19 gene and demethylation of ICR alter IGF2 expression and impair normal kidney development (85).

Above studies suggest a potential pathogenic and therapeutic role for IGF2 in diverse renal disorders, and highlight the need for further investigation into IGF2 signaling pathways and receptor interactions in the kidney to advance early diagnosis, therapeutic strategies and targeted interventions for renal pathologies. The following section explores the effects of IGF2 administration or overexpression in experimental models of renal disease.

IGF2 modulates renal physiology and pathology via a complex receptor network, including IGF2R, IGF1R and IR-A, and downstream signaling pathways such as the PI3K/Akt, MAPK and GSK3 pathways, exhibiting a biphasic regulatory pattern (76,86). Under physiological conditions, IGF2 predominantly interacts with IGF2R, activating the GSK3 signaling pathway and inducing the epigenetic reprogramming of macrophages (8,76). This promotes a metabolic shift toward oxidative phosphorylation (OXPHOS), fosters a macrophagic anti-inflammatory phenotype (76,87). In parallel, IGF2 signaling supports the proliferation of renal tubular epithelial cells, thereby contributing to podocyte cytoskeletal integrity and renal tissue repair (70,88).

By contrast, under pathological conditions, including chronic inflammation, hyperglycemia or loss of genomic imprinting, IGF2 preferentially binds IGF1R and IR-A, leading to sustained activation of the PI3K/Akt-MAPK axis. This signaling cascade disrupts the integrity of the podocyte-slit diaphragm complex and, in synergy with TGF-β1, stimulates collagen deposition and promotes irreversible renal fibrosis (70,89). Furthermore, in contexts involving biallelic IGF2 expression, persistent pro-proliferative signaling may ensue, contributing to proteinuria, glomerulosclerosis and the malignant transformation of renal tissues (90). This receptor-dependent shift in IGF2 signaling cascades represents a central molecular mechanism that governs renal cell fate decisions under both homeostatic and pathological states.

As an important regulator of cell proliferation, metabolic reprogramming and angiogenesis, IGF2 has emerged as a promising therapeutic target, with encouraging progress reported in both preclinical and clinical studies (153–155).

In a preclinical model, the natural compound curcumin has demonstrated potent antitumor effects in bladder cancer by transcriptionally suppressing IGF2, blocking IGF1R/IR substrate 1 phosphorylation and inhibiting the downstream AKT/mTOR signaling cascade. These inhibitory effects are reversed by exogenous IGF2 administration or IGF1R overexpression, highlighting the notable role of IGF2 signaling in tumor progression and validating its therapeutic relevance (156).

Clinically, monoclonal antibodies targeting IGF1R, such as dalotuzumab, and tyrosine kinase inhibitors, such as linsitinib, have shown therapeutic efficacy in select sarcoma subtypes (153). However, these agents have shown limited benefit in breast cancer and non-small cell lung cancer, reflecting the context-dependent nature of IGF signaling and the heterogeneity of downstream pathway activation (157). To overcome compensatory mechanisms, dual-ligand neutralizing antibodies, neutralizing antibodies with different targets have been developed. These include dusigitumab (154), which targets the IGF-1 receptor to block signaling from both IGF-1 and IGF-2, and xentuzumab (155), a dual-IGF-1/IGF-2 ligand-neutralizing antibody that directly binds the ligands themselves. While conceptually promising, their clinical utility has been constrained by the absence of robust predictive biomarkers, which remains a notable barrier to broader application (158).

In pediatric oncology, Wilms' tumor represents a paradigm for IGF2-driven tumorigenesis (159). Using genetically engineered mouse models harboring Wilms' tumor protein deletion and IGF2 overexpression, researchers have successfully recapitulated key features of human WT, including impaired mesenchymal differentiation and persistent ERK1/2 activation. These models provide a robust platform for exploring therapeutic interventions targeting the IGF axis (160).

With respect to angiogenesis, truncated IGF2 variants such as Des(1–6)IGF2 have been shown to promote endothelial cell migration, tube formation and intra-ovarian neovascularization by upregulating IL-6, urokinase plasminogen activator surface receptor and CCL2. Notably, Des(1–6)IGF2 evades inhibition by IGFBP-6, unlike Leu27IGF2, which preferentially binds IGF2R and exhibits minimal angiogenic activity. These findings implicate IGF1R and IR-A as dominant mediators of the pro-angiogenic effects of IGF2 in pathological neovascularization (161).

Despite these promising advances from above experimental and mechanistic studies, several key challenges persist. Ligand redundancy, tissue-specific pathway activation and the lack of reliable biomarkers continue to impede precision targeting of the IGF2 axis (76,162). Future research should focus on developing IGF2-specific inhibitors, optimizing rational combination therapies and identifying context-specific biomarkers, particularly in diseases such as Wilms' tumor and epigenetically-deregulated renal disorders, where IGF2 signaling is pathologically upregulated.

In previous years, with in-depth studies on the biological role of IGF2 and its regulatory mechanisms, the multiple roles of IGF2 in renal development and disease have been revealed. Under normal physiological conditions, IGF2 serves an important role in renal tubular and glomerular formation through precise gene imprinting regulation (24,70). However, under pathological conditions, aberrant expression of IGF2 accelerates the progression of renal fibrosis, DN and renal tumors by activating specific signaling pathways (2,51,136).

Although IGF2 has been validated as a potential biomarker and therapeutic target in renal diseases, a number of mechanistic questions remain unresolved. Future investigations should examine: i) The molecular interplay between IGF2 and regulatory factors such as IGFBPs, TGF-β and VEGF; ii) the spatial and temporal dynamics of receptor activation; and iii) the differential roles of IGF2 in various pathological states. Additionally, the design of IGF2-specific therapies is expected to provide novel strategies for the treatment of kidney disease and associated metabolic disorders.

In conclusion, IGF2 serves an increasingly recognized role in renal biology and pathogenesis. A deeper understanding of its regulatory mechanisms will facilitate the development of precise diagnostic tools and targeted interventions for renal diseases.