Kidney Week

Abstract: FR-PO263

Role of GREMLIN in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Tejedor, Lucia, Cellular Biology in Renal Diseases Laboratory. IIS-Fundación Jiménez Díaz. Universidad Autónoma Madrid, Madrid, Marid, Spain

Lucia Tejedor,

• Cordido, Adrian, Genetics and Developmental Biology of Kidney Diseases, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Adrian Cordido,

• Marquez-Exposito, Laura, Cellular Biology in Renal Diseases Laboratory. IIS-Fundación Jiménez Díaz. Universidad Autónoma Madrid, Madrid, Marid, Spain

Laura Marquez-Exposito,

• Nuñez-Gonzalez, Laura, Genetics and Developmental Biology of Kidney Diseases, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Laura Nuñez-Gonzalez,

• Marchant, Vanessa, Cellular Biology in Renal Diseases Laboratory. IIS-Fundación Jiménez Díaz. Universidad Autónoma Madrid, Madrid, Marid, Spain

Vanessa Marchant,

• Sanz, Ana Belen, Division of Nephrology and Hypertension. IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Madrid, Spain

Ana Belen Sanz,

• Ortiz, Alberto, Division of Nephrology and Hypertension. IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Madrid, Spain

Alberto Ortiz,

• Garcia-Gonzalez, Miguel A., Genetics and Developmental Biology of Kidney Diseases, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Miguel A. Garcia-Gonzalez,

• Ruiz-Ortega, Marta, Cellular Biology in Renal Diseases Laboratory. IIS-Fundación Jiménez Díaz. Universidad Autónoma Madrid, Madrid, Marid, Spain

Marta Ruiz-Ortega,

Background

Autosomal Dominant Polycystic Kidney Disease is a genetic disease caused by PKD1 or PKD2 mutations, which codify for the Polycystin-1 and Polycystin-2 proteins, respectively. ADPKD prevalence is among 1:800 and 1:1000 of live births and is characterized by fluid-filled renal cysts, leading to end-stage renal disease (ESRD). During this process the production of chemokines, cytokines and growth factors by epithelial cells, interstitial fibroblasts and inflammatory cells, such as macrophages, increases. Preclinical studies have described GREMLIN as an important mediator of chronic kidney disease, which could have usefulness as urine biomarker. However, there are no studies about GREMLIN in polycystic kidney disease.

Methods

In an orthologous murine model of polycystic kidney disease (Pkd1^cond/cond;Tam-Cre^-/+) we studied the role of GREMLIN and potential downstream signaling (activation of its receptor VEGFR2 and the Notch pathway) in different stages of renal cystic progression. The polycystic phenotype was induced in lactating mice by administering tamoxifen to the mother on postnatal days 10 and 11, causing a deletion in Pkd1 gene. Studies were performed taking into account different sacrifice points: at 18, 30 and 45 days. In urine and kidney tissue samples from ADPKD patients, GREMLIM levels were evaluated.

Results

In Pkd1^-/+ mutant mice, grem-1 renal expression (the gene encoding GREMLIN protein) was increased from 18 days, with a significant upregulation at 30 days. Grem-1 overexpression was associated with progressive cysts expansion and detriment in renal function measured by BUN. These results were confirmed at the protein level by western blot. Immunohistochemistry revealed positive GREMLIM staining since pre-cystic tubuloepithelial cells, which remained elevated in the tubules at later times. Positive GREMLIN expression was observed in biopsy samples of cysts from ADPKD patients as well as GREMLIN protein presence in urine samples. In the polycystic model, GREMLIN induction was correlated with VEGFR2 activation in the same tubular segments. Cyst formation was also associated with activation of NOTCH1 and NOTCH3.

Conclusion

GREMLIN expression in murine and human polycystic kidney suggests that it may be an important mediator of renal damage progression in ADPKD.