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Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease
Peter Janssens1,2, Jean-Paul Decuypere1, Stéphanie De Rechter1
1PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Insights
Monocyte chemoattractant protein-1 (MCP-1) is elevated in children with autosomal dominant polycystic kidney disease (ADPKD). This finding suggests MCP-1 is an early biomarker for ADPKD severity and a potential therapeutic target.
Area of Science:
- Nephrology
- Pediatric Nephrology
- Molecular Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder leading to kidney failure.
- While ADPKD manifests in adulthood, its origins are in utero.
- Biomarkers like copeptin, EGF, and MCP-1 are linked to adult ADPKD severity but are unstudied in early disease stages.
Purpose of the Study:
- To investigate early-stage biomarkers in pediatric ADPKD.
- To assess plasma copeptin, urinary EGF, and urinary MCP-1 in children with ADPKD.
- To explore the role of MCP-1 in ADPKD pathogenesis.
Main Methods:
- Cross-sectional study comparing pediatric ADPKD patients and healthy controls.
- Measurement of plasma copeptin, urinary EGF, and urinary MCP-1.
- In vitro studies using mouse and human kidney cells, and analysis of fetal kidney tissue.
Main Results:
- Urinary MCP-1 levels were significantly higher in ADPKD patients compared to controls.
- Plasma copeptin and urinary EGF levels were comparable between groups.
- Increased MCP-1 secretion was observed in mutated human tubular cells and knockout mouse cells, with elevated MCP-1 and M2 macrophage infiltration in fetal ADPKD kidneys.
Conclusions:
- Elevated tubular MCP-1 secretion is an early event in ADPKD.
- MCP-1 serves as an early marker for ADPKD disease severity.
- MCP-1 represents a potential therapeutic target for ADPKD.
Introduction:
Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models.
Methods:
In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue.
Results:
Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration.
Conclusion:
An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.
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