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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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Body weight, systolic blood pressure, and organ weights at 4 weeks following UNX/DOCA-salt treatment. (A) No difference in average total body weight among the four groups. (B-D) UNX/DOCA-salt treatment resulted in increased systolic blood pressure, kidney/body weight ratio, and left ventricle/body weight similarly in both podoRac1−/− and Rac1 fl/fl control mice. *P<0.01, **P<0.05
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Figure 8: Body weight, systolic blood pressure, and organ weights at 4 weeks following UNX/DOCA-salt treatment. (A) No difference in average total body weight among the four groups. (B-D) UNX/DOCA-salt treatment resulted in increased systolic blood pressure, kidney/body weight ratio, and left ventricle/body weight similarly in both podoRac1−/− and Rac1 fl/fl control mice. *P<0.01, **P<0.05

Mentions: Albuminuria and progressive glomerulosclerosis are recognized as hallmarks of podocyte injury in the UNX/DOCA-salt-hypertensive rodent model.11 To investigate the effect of podocyte-specific Rac1 deletion in a chronic model of podocyte injury, we employed this injury model in podoRac1−/− and Rac1-fl/fl controls and compared them to sham treatment. Four weeks after UNX/DOCA-salt treatment, the average body weights of all four groups were not significantly different (Figure 8A). As expected, systolic blood pressure, whole kidney weight, and left ventricular heart weight were elevated by treatment in both Rac1 fl/fl and podoRac1−/− mice compared to sham control, with no difference observed between UNX/DOCA-salt treated Rac1 fl/fl and podoRac1−/− (Figure 8B-D).


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)

Body weight, systolic blood pressure, and organ weights at 4 weeks following UNX/DOCA-salt treatment. (A) No difference in average total body weight among the four groups. (B-D) UNX/DOCA-salt treatment resulted in increased systolic blood pressure, kidney/body weight ratio, and left ventricle/body weight similarly in both podoRac1−/− and Rac1 fl/fl control mice. *P<0.01, **P<0.05
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 8: Body weight, systolic blood pressure, and organ weights at 4 weeks following UNX/DOCA-salt treatment. (A) No difference in average total body weight among the four groups. (B-D) UNX/DOCA-salt treatment resulted in increased systolic blood pressure, kidney/body weight ratio, and left ventricle/body weight similarly in both podoRac1−/− and Rac1 fl/fl control mice. *P<0.01, **P<0.05
Mentions: Albuminuria and progressive glomerulosclerosis are recognized as hallmarks of podocyte injury in the UNX/DOCA-salt-hypertensive rodent model.11 To investigate the effect of podocyte-specific Rac1 deletion in a chronic model of podocyte injury, we employed this injury model in podoRac1−/− and Rac1-fl/fl controls and compared them to sham treatment. Four weeks after UNX/DOCA-salt treatment, the average body weights of all four groups were not significantly different (Figure 8A). As expected, systolic blood pressure, whole kidney weight, and left ventricular heart weight were elevated by treatment in both Rac1 fl/fl and podoRac1−/− mice compared to sham control, with no difference observed between UNX/DOCA-salt treated Rac1 fl/fl and podoRac1−/− (Figure 8B-D).

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