Abstract: TH-PO082

Plasminogen Activator Inhibitor-1 (PAI-1) Modulates Parietal Epithelial Cell (PEC) Activation and Migration after Podocyte Injury

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Li, Xin, The Medicine College of Shanghai JiaoTong University, Shanghai, China
  • Moeller, Marcus J., University of Aachen, RWTH, Aachen, Germany
  • Matsusaka, Taiji, Tokai University School of Medicine, Isehara, KANAGAWA, Japan
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Parietal epithelial cells (PECs) can migrate on to the glomerular tuft and serve as either progenitor cells to replace podocytes or profibrotic cells to secret matrix in response to injury. Claudin-1 is expressed on all PECs, while CD44 is expressed on activated PECs. PAI-1 affects matrix turnover, cell migration and mediates renal fibrosis. After glomerular injury, PAI-1 expression on PECs increases. We aimed to study effects of PAI-1 on PECs migration, activation and transdifferentiation after podocyte injury.

Methods

NEP25 mice express human CD25 only on podocyte, and podocyte injury is induced by exogenous immunotoxin (LMB2). By mating NEP25/PAI-1loxP with PEC-rtTA/ PAI-1loxP transgenic mice, we generated inducible PEC specific PAI-1 knockdown mice (PAI-1 KD, n=8) and control (WT, n=10). All mice underwent doxycycline induction at 9 weeks old followed by LMB2 injection at 10 weeks, and were sacrificed 10 days later.

Results

LMB2 induced similar albuminuria and segmental glomerular sclerosis in WT and PAI-1 KD mice. Podocyte density, measured by WT-1 staining, was similar in the two groups (WT 3.9±0.8 vs PAI-1 KD 3.7±0.5 /104 um2), but synaptopodin expression was higher in PAI-1 KD (18.7 ±16.7%) than WT (5.3±2.4%, P<0.05). PAI-1 KD induced more CD44+ PECs on glomerular tuft (2.8±0.8 vs WT 1.3±1.2%, P<0.05), while WT showed more claudin-1+ cells on the tuft (4.14±1.57% vs. 2.51±0.87%,WT vs. PECs PAI-1 KD P<0.05). By double staining, we assessed the proportion of PECs expresses nephrin, a podocyte differentiation marker, finding 14.1±4.4% of claudin-1+ cells also expressing nephrin in WT, similar in PAI-1 KD (11.0±4.0%, pNS). CD44+ cells expressing nephrin were also similar in the two groups (WT 17.7±9.2 vs. PAI KD 13.0±5.9%, pNS).

Conclusion

We conclude that knockdown of PAI-1 increased the presence of activated PEC on the tuft and preserved podocyte differentiation, but does not affect PECs transdifferentiation to podocyte.

Funding

  • NIDDK Support