How does the liver-secreted factor LECT2 affect renal fibrosis by regulating endoplasmic reticulum stress and EGFR signaling?

1. What role does LECT2 play in renal fibrosis progression?

Renal fibrosis is a common pathological feature of various chronic kidney diseases progressing to end-stage, with core mechanisms involving persistent inflammatory responses, myofibroblast activation, and excessive extracellular matrix deposition. Recent studies have found that liver-derived secretory factors play a crucial role in inter-organ communication and remote tissue pathological regulation. Leukocyte cell-derived chemotaxin-2 (LECT2), a cytokine primarily secreted by hepatocytes, exhibits significant changes in expression patterns during renal structural remodeling. In normal renal tissue, LECT2 is mainly localized in the renal tubulointerstitial region; during fibrosis, its expression expands along vascular structures, suggesting its potential involvement in the dynamic regulation of the renal microenvironment. Loss-of-function experiments (Lect2 knockout) in mouse models confirmed that LECT2 deficiency significantly alleviates unilateral ureteral obstruction-induced renal fibrosis, manifested by reduced tubular dilation, approximately 40% less collagen deposition, and significant downregulation of myofibroblast activation markers (α-SMA, type I collagen).

2. How does LECT2 engage in cross-talk through ER stress and EGFR signaling pathways?

In-depth mechanistic studies reveal that LECT2's pro-fibrotic effects are not directly on fibroblasts but are mediated through complex signaling networks, particularly via interactions between endoplasmic reticulum (ER) stress response and epidermal growth factor receptor (EGFR) pathways.

1. Dual regulation of ER stress: ER stress is a critical cellular response to the accumulation of misfolded proteins, and its excessive activation may lead to apoptosis. Studies show that in LECT2 knockout mice, the baseline expression of the pro-apoptotic transcription factor CHOP is higher and further increases upon treatment with ER stress inducers (e.g., tunicamycin). In contrast, fibrotic kidneys in wild-type mice exhibit upregulated CHOP but depleted molecular chaperone GRP78, indicating sustained stress responses. This disparity suggests that LECT2 may suppress early adaptive ER stress responses. In acute stress models, Lect2 knockout mice display milder tubular injury and stronger CHOP expression (mainly localized in endothelial cells), implying that LECT2 deficiency may enhance early ER stress responses, conferring "preconditioning" resistance to endothelial cells against subsequent damage, thereby mitigating fibrosis progression.

2. Activation of EGFR/PI3K/AKT survival signaling: Cellular studies elucidate LECT2's direct targets. Immunoprecipitation experiments confirm that LECT2 directly binds to EGFR. Overexpression of LECT2 in endothelial cells significantly enhances phosphorylation of EGFR and its downstream PI3K/AKT pathway, whether induced by tunicamycin-mediated ER stress or TGF-β1-stimulated pro-fibrotic environments. This signaling activation has clear biological consequences: it effectively suppresses caspase-dependent apoptotic cascades, reduces early apoptosis rates, and promotes sustained secretion of pro-fibrotic factors like vascular endothelial growth factor A (VEGFA). Thus, LECT2 indirectly drives renal fibrosis by maintaining endothelial cell survival under stress and activating their secretory phenotype.

3. What are the key applications of recombinant human LECT2 protein in related research?

To thoroughly dissect LECT2's functions and molecular mechanisms, high-purity recombinant human LECT2 protein is an indispensable tool with multiple applications in basic and translational research:

1. Gain-of-function studies and dose-response validation: In vitro cell culture systems, direct addition of recombinant LECT2 at varying concentrations can precisely mimic its paracrine/endocrine effects in vivo, verifying whether observed knockout phenotypes can be reversed by exogenous protein and establishing dose-response relationships.

2. Signaling pathway mechanism elucidation: Treating specific cells (e.g., endothelial cells, renal tubular epithelial cells, or fibroblasts) with recombinant LECT2, combined with pathway inhibitors, systematically maps LECT2's downstream signaling networks, clarifying the necessity and sufficiency of its activation of EGFR, PI3K/AKT, and other pathways.

3. Receptor interaction and binding properties: Recombinant protein can be used in surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and other techniques to quantitatively measure LECT2's binding affinity (KD) with EGFR or other potential receptors and explore its structural domain basis.

4. Disease model intervention studies: In animal fibrosis models, systemic or local delivery of recombinant LECT2 can directly assess its role as a pathogenic factor in disease progression or explore its potential as a therapeutic target.

4. What insights does the LECT2-mediated signaling network provide for understanding organ fibrosis?

This study reveals an elegant example of liver-derived secretory factors remotely regulating renal fibrosis. As a signaling hub, LECT2 establishes a unique balance between cell survival and tissue remodeling by suppressing adaptive ER stress (possibly sacrificing early apoptosis of some cells for overall tissue protection) and persistently activating EGFR/PI3K/AKT survival pathways (protecting endothelial cells but inducing pro-fibrotic factor secretion). This "survival-fibrosis" paradox highlights the complexity of signaling pathways and cell-type-specific outcomes in pathological processes.

5. Summary and Future Perspectives

In summary, liver-secreted LECT2 binds to renal endothelial cell EGFR, activating PI3K/AKT survival signaling, inhibiting apoptosis and adaptive ER stress responses, but simultaneously promoting endothelial cell secretion of VEGFA and other factors, indirectly driving myofibroblast activation and extracellular matrix deposition, ultimately exacerbating renal fibrosis. This mechanism underscores the importance of inter-organ communication in fibrotic diseases. Future research using tools like recombinant human LECT2 protein may further explore its roles in different cell types, the impact of post-translational modifications (e.g., glycosylation), and the development of small-molecule inhibitors or neutralizing antibodies targeting LECT2-EGFR interactions, potentially offering new anti-fibrotic strategies. Additionally, this study suggests that finely tuning (rather than completely inhibiting) ER stress responses may be a promising novel approach for tissue protection.

6. Which manufacturers provide recombinant human LECT2 protein?

Hangzhou Starter Biotech Co., Ltd. has independently developed "Human LECT2 Protein (His tag)" (product name: Human LECT2, His tag; catalog number: S0A0096), a multifunctional cytokine/chemokine with high bioactivity, purity, and stability. This product is recombinantly expressed in mammalian systems with a C-terminal His tag and holds significant value in liver regeneration, inflammatory regulation, metabolic diseases, and tumor immunology research.

Technical support: We provide comprehensive product documentation, including purity analysis reports, functional validation data, experimental protocols, and expert consultation, supporting advancements in liver biology, immunology, and metabolic research.

Hangzhou Starter Biotech Co., Ltd. is committed to delivering high-quality, high-value biological reagents and solutions to global innovators and research institutions. For details on "Human LECT2 Protein (His tag)" (catalog S0A0096) or sample requests, please contact us.

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