Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis
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Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis. / Meyer-Schwesinger, Catherine; Dehde, Silke; Sachs, Marlies; Mathey, Sabrina; Arefi, Kazem; Gatzemeier, Stefan; Balabanov, Stefan; Becker, Jan U; Thaiss, Friedrich; Meyer, Tobias N.
In: AM J PHYSIOL-RENAL, Vol. 303, No. 7, 01.10.2012, p. F1015-25.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis
AU - Meyer-Schwesinger, Catherine
AU - Dehde, Silke
AU - Sachs, Marlies
AU - Mathey, Sabrina
AU - Arefi, Kazem
AU - Gatzemeier, Stefan
AU - Balabanov, Stefan
AU - Becker, Jan U
AU - Thaiss, Friedrich
AU - Meyer, Tobias N
PY - 2012/10/1
Y1 - 2012/10/1
N2 - Podocyte foot process retraction is a hallmark of proteinuric glomerulonephritis. Cytoskeletal rearrangement causes a redistribution of slit membrane proteins from the glomerular filtration barrier towards the cell body. However, the underlying signaling mechanisms are presently unknown. Recently, we have developed a new experimental model of immune-mediated podocyte injury in mice, the antipodocyte nephritis (APN). Podocytes were targeted with a polyclonal antipodocyte antibody causing massive proteinuria around day 10. Rho-kinases play a central role in the organization of the actin cytoskeleton of podocytes. We therefore investigated whether inhibition of Rho-kinases would prevent podocyte disruption. C57/BL6 mice received antipodocyte serum with or without daily treatment with the specific Rho-kinase inhibitor HA-1077 (5 mg/kg). Immunoblot analysis demonstrated activation of Rho-kinase in glomeruli of antipodocyte serum-treated mice, which was prevented by HA-1077. Increased Rho-kinase activity was localized to podocytes in APN mice by immunostainings against the phosphorylated forms of Rho-kinase substrates. Rho-kinase inhibition significantly reduced podocyte loss from the glomerular tuft. Periodic acid staining demonstrated less podocyte hypertrophy in Rho-kinase-inhibited APN mice, despite similar amounts of immune complex deposition. Electron microscopy revealed reduced foot process effacement compared with untreated APN mice. Internalization of the podocyte slit membrane proteins nephrin and synaptopodin was prevented by Rho-kinase inhibition. Functionally, Rho-kinase inhibition significantly reduced proteinuria without influencing blood pressure. In rats with passive Heymann nephritis and human kidney biopsies from patients with membranous nephropathy, Rho-kinase was activated in podocytes. Together, these data suggest that increased Rho-kinase activity in the podocyte may be a mechanism for in vivo podocyte foot process retraction.
AB - Podocyte foot process retraction is a hallmark of proteinuric glomerulonephritis. Cytoskeletal rearrangement causes a redistribution of slit membrane proteins from the glomerular filtration barrier towards the cell body. However, the underlying signaling mechanisms are presently unknown. Recently, we have developed a new experimental model of immune-mediated podocyte injury in mice, the antipodocyte nephritis (APN). Podocytes were targeted with a polyclonal antipodocyte antibody causing massive proteinuria around day 10. Rho-kinases play a central role in the organization of the actin cytoskeleton of podocytes. We therefore investigated whether inhibition of Rho-kinases would prevent podocyte disruption. C57/BL6 mice received antipodocyte serum with or without daily treatment with the specific Rho-kinase inhibitor HA-1077 (5 mg/kg). Immunoblot analysis demonstrated activation of Rho-kinase in glomeruli of antipodocyte serum-treated mice, which was prevented by HA-1077. Increased Rho-kinase activity was localized to podocytes in APN mice by immunostainings against the phosphorylated forms of Rho-kinase substrates. Rho-kinase inhibition significantly reduced podocyte loss from the glomerular tuft. Periodic acid staining demonstrated less podocyte hypertrophy in Rho-kinase-inhibited APN mice, despite similar amounts of immune complex deposition. Electron microscopy revealed reduced foot process effacement compared with untreated APN mice. Internalization of the podocyte slit membrane proteins nephrin and synaptopodin was prevented by Rho-kinase inhibition. Functionally, Rho-kinase inhibition significantly reduced proteinuria without influencing blood pressure. In rats with passive Heymann nephritis and human kidney biopsies from patients with membranous nephropathy, Rho-kinase was activated in podocytes. Together, these data suggest that increased Rho-kinase activity in the podocyte may be a mechanism for in vivo podocyte foot process retraction.
KW - Animals
KW - Antigen-Antibody Complex
KW - Glomerulonephritis
KW - Kidney
KW - Male
KW - Mice
KW - Nephritis
KW - Podocytes
KW - Proteinuria
KW - Rats
KW - Rats, Sprague-Dawley
KW - Signal Transduction
KW - rho-Associated Kinases
U2 - 10.1152/ajprenal.00380.2011
DO - 10.1152/ajprenal.00380.2011
M3 - SCORING: Journal article
C2 - 22811486
VL - 303
SP - F1015-25
JO - AM J PHYSIOL-RENAL
JF - AM J PHYSIOL-RENAL
SN - 1931-857X
IS - 7
ER -