Kidney Week

Abstract: TH-PO1086

Cell-Specific Role of Platelet-Derived Growth Factor Subunit B (PDGF-B) in Kidney Fibrosis

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Klinkhammer, Barbara Mara, Institute of Pathology, RWTH Aachen University Hospital, Aachen, NRW, Germany

Barbara Mara Klinkhammer, PhD

• Buhl, Eva Miriam, Electron Microscopy Facility, RWTH Aachen University Hospital, Aachen, NRW, Germany

Eva Miriam Buhl

• Caspers, Tim, Institute of Pathology, RWTH Aachen University Hospital, Aachen, NRW, Germany

Tim Caspers, MSc

• Wong, Dickson WL, Institute of Pathology, RWTH Aachen University Hospital, Aachen, NRW, Germany

Dickson WL Wong, PhD

• Goedertier, Michaël, Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, NRW, Germany

Michaël Goedertier, MSc

• Hölscher, David Laurin, Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, NRW, Germany

David Laurin Hölscher, MD

• Bülow, Roman David, Institute of Pathology, RWTH Aachen University Hospital, Aachen, NRW, Germany

Roman David Bülow

• Boor, Peter, Institute of Pathology, RWTH Aachen University Hospital, Aachen, NRW, Germany

Peter Boor, MD, PhD

Background

Kidney fibrosis is a critical pathological process in progressive kidney diseases. Platelet-derived growth factor (PDGF) has been implicated in the development and progression of kidney fibrosis, yet the exact cellular origins remain unclear.

Methods

Three transgenic mouse lines were generated with cell-specific Pdgfb deletion in platelets, fibroblasts or epithelial cells. Spontaneous phenotypes were analyzed in young and aged male and female animals. Kidney fibrosis was induced by unilateral ureteral obstruction, ischemia-reperfusion injury or 0.2% adenine diet. Kidney function was analyzed by blood and urine analysis and perfused kidneys were investigated with histological, immunohistochemical, and immunofluorescence stainings, molecular biology and protein biochemical analyses.

Results

Mice with megakaryocyte- and platelet-specific Pdgfb deletion exhibited neither a spontaneous kidney phenotype nor altered fibrosis development in disease models, challenging the conventional understanding of fibrosis as wound healing, in which “platelet-derived” growth factors play a major role. PDGF-B, and its receptor PDGFR-β, are expressed by mesenchymal cells in the kidneys, and some studies suggested potential autocrine effects. Deletion of Pdgfb in mesenchymal cells had no effects on normal development, aging or disease model progression, suggesting negligible effects of autocrine signaling in the kidney. In contrast, mice with Pdgfb deletion in kidney tubular epithelial cells exhibited smaller kidneys with reduced interstitium, particularly in the medulla, without compromising overall development or physiological kidney function, even at advanced ages. Furthermore, in three distinct models featuring tubular injury from various causes, mice lacking Pdgfb in tubular cells displayed significantly reduced fibrosis. The diminished paracrine PDGF-B/PDGFR-β signaling between tubules and peritubular fibroblasts led to decreased activation and proliferation of peritubular PDGFR-β+ cells, ultimately altering the profibrotic niche in the interstitium.

Conclusion

Our findings unveil a PDGF-driven molecular mechanism of paracrine cellular crosstalk mediating the transition from tubular injury to interstitial fibrosis.