Kidney Week

Abstract: FR-PO294

Early Cyst Formation Leads to the Development of an Inflammatory Microenvironment and Tissue Remodeling in Polycystic Kidney Disease

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

• Chakraborty, Anubhav, University of Kansas Medical Center, Kansas City, Kansas, United States

Anubhav Chakraborty,

• Parnell, Stephen C., University of Kansas Medical Center, Kansas City, Kansas, United States

Stephen C. Parnell,

• Zhang, Yan, University of Kansas Medical Center, Kansas City, Kansas, United States

Yan Zhang,

• Daniel, Emily A., University of Kansas Medical Center, Kansas City, Kansas, United States

Emily A. Daniel,

• Raman, Archana, University of Kansas Medical Center, Kansas City, Kansas, United States

Archana Raman,

• Reif, Gail, University of Kansas Medical Center, Kansas City, Kansas, United States

Gail Reif,

• Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States

Darren P. Wallace,

Background

Polycystic kidney disease (PKD) is a genetic disorder characterized by the formation and growth of numerous fluid-filled cysts. BRAF, a kinase that activates MEK-ERK signaling, is a central intermediate for cAMP-induced cell proliferation and cyst growth in PKD. Recently, we showed that collecting duct (CD)-specific expression of active BRAF^V600E, a common activating mutation (BRaf^CD), was sufficient to induce renal cyst formation in an otherwise normal mouse. A key pathological feature of PKD is the development of interstitial inflammation and fibrosis, leading to a decline in renal function. Our hypothesis is that cyst formation induces an inflammatory microenvironment early in renal cystic disease.

Methods

To examine changes in gene expression due to cyst formation, we performed RNA sequencing on 3-week-old cystic kidneys from BRaf^CD mice and Pkd1^RC/RC mice, an orthologous slowly progressive model of PKD. Kidneys from 3-week-old wildtype mice were used as controls. Pathway analysis was used to identify common pathways affected during initial cyst formation due to active BRAF-MEK-ERK signaling and mutated Pkd1.

Results

We found that 566 out of 641 differentially expressed genes (DEGs) in the BRaf^CD kidneys were also changed in the Pkd1^RC/RC kidneys (out of 840). Enrichment analysis indicated that inflammation, cytokine response, tissue fibrosis, and remodeling were some of the top activated pathways and cellular functions (FDR < 0.05; Z-score > 2). 88 of the 566 common DEGs were identified as inflammatory genes (Fold Change ≥ 1.5; FDR < 0.05), including elevated expression of tumor necrosis factor-alpha (TNFα), toll-like receptor 8, and interleukin-34. The renal tubule injury marker neutrophil gelatinase-associated lipocalin (NGAL, LCN2) and tissue remodeling factors such as MMP-7, mucins (MUC5B, MUC15), lipase family member K, glutathione peroxidase 5, and protease inhibitors (cystatin-11 and -12, serine peptidase inhibitor) were also upregulated.

Conclusion

Renal cyst initiation due to active BRAF or mutated Pkd1 was associated with elevated gene expression of markers for inflammation and tissue remodeling prior to the overt cystic disease, suggesting that cystic cells contribute to early development of an inflammatory microenvironment.

Funding

• NIDDK Support