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Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.

Blattner SM, Hodgin JB, Nishio M, Wylie SA, Saha J, Soofi AA, Vining C, Randolph A, Herbach N, Wanke R, Atkins KB, Gyung Kang H, Henger A, Brakebusch C, Holzman LB, Kretzler M - Kidney Int. (2013)

Bottom Line: Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood.Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state.However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.

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Related in: MedlinePlus

Loss of podocyte-specific Rac1 protects against induction of podocyte foot process effacement by protamine sulfate. (A) Transmission EM of glomerular capillary walls of floxed control mice after perfusion with HBSS control (top left) and protamine sulfate (top right) demonstrates partial foot process effacement (arrowheads). Glomerular capillary walls from podoRac1−/− mice after perfusion with HBSS control (bottom left) and protamine sulfate (bottom right) shows no qualitative difference in foot process morphology. Results are representative of 6-8 mice per group. ×7900 magnification (B) Filtration slit frequency per micron as seen by transmission EM reflects the morphologic interpretation. *P<0.05
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Figure 7: Loss of podocyte-specific Rac1 protects against induction of podocyte foot process effacement by protamine sulfate. (A) Transmission EM of glomerular capillary walls of floxed control mice after perfusion with HBSS control (top left) and protamine sulfate (top right) demonstrates partial foot process effacement (arrowheads). Glomerular capillary walls from podoRac1−/− mice after perfusion with HBSS control (bottom left) and protamine sulfate (bottom right) shows no qualitative difference in foot process morphology. Results are representative of 6-8 mice per group. ×7900 magnification (B) Filtration slit frequency per micron as seen by transmission EM reflects the morphologic interpretation. *P<0.05

Mentions: Protamine sulfate in rodent models results in alterations in podocyte shape characterized by foot process effacement within minutes of perfusion. This is thought to be an actin dependent process triggered through neutralization of anionic charge and/or disruption of podocyte-basement membrane interactions.10 Infusing control mice with protamine sulfate resulted in morphologically distinct foot process effacement (Figure 7A, upper panels). Calculation of the podocyte filtration slit frequency (FSF) revealed a significant reduction by approximately 27% (Figure 7B). In contrast, the podocyte foot process morphology appeared unchanged by protamine sulfate perfusion in podoRac1−/− mice (Figure 7A, lower panels), and FSF was not significantly reduced after 15 min. of perfusion (Figure 7B).


Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.

Blattner SM, Hodgin JB, Nishio M, Wylie SA, Saha J, Soofi AA, Vining C, Randolph A, Herbach N, Wanke R, Atkins KB, Gyung Kang H, Henger A, Brakebusch C, Holzman LB, Kretzler M - Kidney Int. (2013)

Loss of podocyte-specific Rac1 protects against induction of podocyte foot process effacement by protamine sulfate. (A) Transmission EM of glomerular capillary walls of floxed control mice after perfusion with HBSS control (top left) and protamine sulfate (top right) demonstrates partial foot process effacement (arrowheads). Glomerular capillary walls from podoRac1−/− mice after perfusion with HBSS control (bottom left) and protamine sulfate (bottom right) shows no qualitative difference in foot process morphology. Results are representative of 6-8 mice per group. ×7900 magnification (B) Filtration slit frequency per micron as seen by transmission EM reflects the morphologic interpretation. *P<0.05
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815690&req=5

Figure 7: Loss of podocyte-specific Rac1 protects against induction of podocyte foot process effacement by protamine sulfate. (A) Transmission EM of glomerular capillary walls of floxed control mice after perfusion with HBSS control (top left) and protamine sulfate (top right) demonstrates partial foot process effacement (arrowheads). Glomerular capillary walls from podoRac1−/− mice after perfusion with HBSS control (bottom left) and protamine sulfate (bottom right) shows no qualitative difference in foot process morphology. Results are representative of 6-8 mice per group. ×7900 magnification (B) Filtration slit frequency per micron as seen by transmission EM reflects the morphologic interpretation. *P<0.05
Mentions: Protamine sulfate in rodent models results in alterations in podocyte shape characterized by foot process effacement within minutes of perfusion. This is thought to be an actin dependent process triggered through neutralization of anionic charge and/or disruption of podocyte-basement membrane interactions.10 Infusing control mice with protamine sulfate resulted in morphologically distinct foot process effacement (Figure 7A, upper panels). Calculation of the podocyte filtration slit frequency (FSF) revealed a significant reduction by approximately 27% (Figure 7B). In contrast, the podocyte foot process morphology appeared unchanged by protamine sulfate perfusion in podoRac1−/− mice (Figure 7A, lower panels), and FSF was not significantly reduced after 15 min. of perfusion (Figure 7B).

Bottom Line: Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood.Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state.However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.

Show MeSH
Related in: MedlinePlus