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Abstract: TH-PO991

FK506 Binding Protein 12 (FKBP12) Is Highly Expressed in Glomerular Podocyte in Kidney: FKBP12 in Podocyte Is Co-Localized with Actin Cytoskeleton and Is Re-Distributed in Injured Podocytes

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Yasuda, Hidenori, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Fukusumi, Yoshiyasu, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Zhang, Ying, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Kawachi, Hiroshi, Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Background

FKBP12, a 12 kDa cytoplasmic immunophilin, was identified as a binding protein of FK506 (tacrolimus). Tacrolimus and rapamycin bind to FKBP12 and exhibit immunosuppressant effect through inhibition of calcineurin and mTOR, respectively in T cells. FKBP12 is reported to be expressed in various organs, and the distribution is associated with side effects of these drugs. It is also known that FKBP12 functions independently of these immunosuppressants; for example, FKBP12 binds to TGF-b type 1 receptor and inhibits its signaling. However, the localization and the physiological function of FKBP12 in kidney are not well elucidated.

Methods

mRNA expression of FKBP12 in several tissues and cultured podocytes was analyzed with RT-PCR and its precise localization was investigated with the immuno-histochemical analyses with a specific antibody produced in a rabbit immunized with specific peptide. The FKBP12 expression in injured podocytes was also analyzed.

Results

FKBP12 mRNA expression in whole kidney was lower than in other organ materials such as cerebrum, liver, heart and lung, but the high expression was detected in glomeruli. The histochemical analysis with rat kidney section showed FKBP12 was highly expressed in glomeruli. Dual labeling staining with glomerular cell markers showed the FKBP12 expression in glomeruli was restricted in podocyte and the staining in podocyte was mainly detected at the cytoplasm close to cell membrane. FKBP12 staining in cultured pocoytes was colocalized with cytoskeletal actin. mRNA expression of FKBP12 in glomeruli was downregulated at the initiation phase of nephrotic models, anti-nephrin antibody-induced nephropathy (20.0% to normal, P<0.001) and in PAN nephropathy, a mimic of MCNS (26.0% P <0.001). Immuno-staining of FKBP12 was clearly lowered when proteinuria peaked in PAN nephropathy (staining score, 2.7 vs 3.5 of normal, P<0.05), and in ADR nephropathy, a mimic of FSGS (score 2.9, P<0.05). FKBP12 staining was clearly decreased in the human cultured podocytes treated with ADR (67% to normal; P<0.05) and with serum free medium (61% P<0.05).

Conclusion

FKBP12 is mainly expressed along cytoskeletal actin in podocyte and its altered expression might be associated with cytoskeletal remodeling in podocyte injury.

Funding

  • Government Support - Non-U.S.