Introduction
Discovered in the mid-1990s, CXCL12, initially known as pre-B cell growth-stimulating factor and later as stromal cell-derived factor-1 (SDF-1), has been identified as a chemokine with six splice variants in humans and three in mice. CXCL12 interacts primarily with CXCR4 but also with CXCR7, influencing migration and adhesion of various cell types, including hematopoietic progenitors, endothelial cells (ECs), and leukocytes. CXCL12 is crucial in processes ranging from embryogenesis to inflammation, organ injury regeneration, and tumor metastasis.
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CXCL12 is significantly involved in renal development, particularly in the formation of renal vasculature. It also plays a role in attracting target cells and inducing cellular interactions through various signaling pathways. Increasing evidence points to CXCL12's involvement in diverse kidney diseases, including AKI, DKD, lupus nephritis, kidney transplantation, and RCC, although the exact mechanisms remain unclear.
Fig. 1 Correlation between CXCL12 and AKI (Song A.; et al. 2021).
The Role of CXCL12 in Nephrogenesis
CXCL12 is crucial for angiogenesis and organogenesis, particularly in renal development. During glomerular formation, CXCL12 is expressed in stromal cells and podocytes, whereas CXCR4 is present in the nephrogenic zone throughout embryogenesis. Early embryonic stages exhibit strong CXCR4 expression in the ureteric bud and pretubular aggregates, which later shifts to cap mesenchyme, indicating its involvement in nephrogenesis.
Notably, CXCL12 and CXCR4 interaction is essential for glomerular endothelial cell (EC) survival and proliferation, with signaling pathways like p44/42 mitogen-activated protein kinase (MAPK) and Akt being activated. Evidence also suggests an autocrine pathway in which CXCL12/CXCR4 signaling enhances angiogenesis by promoting endothelial nitric oxide synthase (eNOS) and VEGF expression.
Despite these findings, the precise molecular mechanisms underlying CXCL12/CXCR4-mediated nephrogenesis remain unclear, necessitating further research.
The Interplay Between CXCL12 and Kidney Diseases
CXCL12 and Acute Kidney Injury (AKI)
AKI, characterized by a sudden decline in renal function, often involves ischemia-reperfusion injury (IRI), which disrupts renal vascular integrity and promotes inflammation. CXCL12 plays a pivotal role in renal recovery from AKI, as demonstrated by its increased expression in the kidney post-IRI.
CXCL12 promotes angiogenesis and tubular cell proliferation by attracting bone marrow-derived cells (BMCs) and side population (SP) cells to the injured kidney. These cells differentiate into ECs and tubular epithelial cells (TECs), facilitating renal regeneration. Additionally, signaling pathways like PI3K, JNK/STAT, and MAPK/Erk are involved in CXCL12/CXCR4-mediated renoprotection.
Moreover, CXCL12/CXCR4 axis mediates inflammatory infiltration in AKI, affecting neutrophils, T-cells, and macrophages. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as saxagliptin, sustain CXCL12 expression and enhance its renoprotective effects via pathways like Kim-1/STAT-3/HIF-1α/VEGF.
CXCL12 and Diabetic Kidney Disease (DKD)
DKD, a common complication of diabetes, is characterized by podocyte injury and mesangial expansion. The CXCL12/CXCR4 axis has a dual role in DKD, contributing to both renal protection and disease progression.
On the protective side, CXCL12/CXCR4 interaction promotes podocyte survival, reduces TEC death, and inhibits mesangial expansion. DPP-4 inhibitors enhance CXCL12 expression, offering antifibrotic and antioxidant benefits.
Conversely, CXCL12/CXCR4 axis can impair podocyte progenitor cell differentiation and increase inflammation, exacerbating DKD. Blocking CXCL12/CXCR4 has shown potential in reducing glomerulosclerosis and albuminuria.
CXCL12 and Lupus Nephritis
Lupus nephritis, a severe manifestation of systemic lupus erythematosus, involves immune complex deposition and inflammation. CXCL12, by attracting antibody-secreting cells (ASCs) and other immune cells, plays a significant role in its pathogenesis.
Upregulation of CXCL12 in podocytes attracts CXCR4-positive ASCs, facilitating autoantibody deposition. CXCL12/CXCR4 interaction also triggers inflammatory signaling pathways like PI3K/AKT, NF-κB, and JAK/STAT, exacerbating renal damage.
Conversely, neutralizing CXCL12 or blocking CXCR4 has been shown to mitigate lupus nephritis, reducing proteinuria and immune cell infiltration, suggesting therapeutic potential.
CXCL12 and Kidney Transplantation
Kidney transplantation is the optimal treatment for end-stage renal disease (ESRD), but chronic allogeneic nephropathy (CAN) remains a challenge. CXCL12/CXCR4 axis plays a complex role in CAN, influencing fibrosis, immune cell infiltration, and graft survival.
CXCL12 promotes renal allograft fibrosis and epithelial-mesenchymal transition (EMT) by activating pathways like Wnt/β-catenin. However, CXCL12 also aids in BMCs and MSCs homing to the kidney, facilitating graft repair and function.
Genetic polymorphisms of CXCL12 in donors can affect transplant outcomes, indicating the need for careful donor selection. Overall, the CXCL12/CXCR4 axis is a crucial regulator in kidney transplantation, balancing between graft protection and damage.
CXCL12 and Renal Cell Carcinoma (RCC)
Clear cell RCC (cc-RCC), the most common RCC subtype, often involves von Hippel-Lindau (VHL) gene inactivation, leading to HIF-1α accumulation and upregulated CXCL12/CXCR4 expression. This axis contributes to RCC growth, angiogenesis, and metastasis.
High CXCL12/CXCR4 expression correlates with poor prognosis, increased tumor grade, and metastasis. CXCL12 promotes RCC cell adhesion to vascular ECs and tissue invasion, while targeting the CXCL12/CXCR4 axis shows promise in reducing metastasis and improving survival.
Given these findings, CXCL12/CXCR4 represents a potential therapeutic target for RCC, offering new avenues for treatment and management.
Conclusion
CXCL12, through its interaction with CXCR4 and CXCR7, plays a multifaceted role in both renal development and kidney diseases. While it promotes renal vasculature formation and cell proliferation during development, its role in kidney diseases is complex and context-dependent. The CXCL12/CXCR4 axis supports renal recovery in AKI, has dualistic effects in DKD, and contributes to autoimmune and inflammatory processes in lupus nephritis. In kidney transplantation, it affects graft survival and fibrosis, while in RCC, it facilitates tumor growth and metastasis.
Understanding the intricate mechanisms of CXCL12 in these diverse settings offers promising therapeutic avenues. However clinical trials and research are needed to fully harness its therapeutic potential in renal diseases. Future studies involve unraveling the complex molecular interactions of CXCL12, translating these findings into clinical applications, and ultimately improving renal disease treatment and patient outcomes.
Reference
- Song A., et al. The role of CXCL12 in kidney diseases: a friend or foe?. Kidney Diseases. 2021, 7(3): 176-185.
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