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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

Progressive glomerulosclerosis in podoCdc42−/− but not podoRac1−/− mice by light microscopy (PAS staining at 20× and 40× magnification). (A, B) Floxed control mice demonstrate normal tubulointerstitial and glomerular morphology at 3-4 weeks of age. (C, D) podoRac1−/− tubulointerstitial and glomerular morphology at 12 months of age is indistinguishable from control. Podocyte-specific loss of Cdc42 results in tubular protein casts and injury (E) as well as focal segmental glomerulosclerosis in a minority of glomeruli (F) at 3-4 weeks of age.
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Figure 2: Progressive glomerulosclerosis in podoCdc42−/− but not podoRac1−/− mice by light microscopy (PAS staining at 20× and 40× magnification). (A, B) Floxed control mice demonstrate normal tubulointerstitial and glomerular morphology at 3-4 weeks of age. (C, D) podoRac1−/− tubulointerstitial and glomerular morphology at 12 months of age is indistinguishable from control. Podocyte-specific loss of Cdc42 results in tubular protein casts and injury (E) as well as focal segmental glomerulosclerosis in a minority of glomeruli (F) at 3-4 weeks of age.

Mentions: Kidney morphology at 4 weeks of age was examined by light microscopy (Figure 2). Compared to floxed Cdc42 or Rac1 controls (Figure 2, A and B), podoRac1−/− kidneys (Figure 2, C and D) showed no alteration in glomerular or tubulo-interstitial morphology for up to 12 months of age. In contrast, podoCdc42−/− mice displayed progressive focal and global glomerulosclerosis accompanied by diffuse tubular dilatation with protein casts and tubular injury (Figure 2, E and F). Podocytes often appeared prominent and vacuolated. Segmentally sclerotic portions contained abundant extracellular matrix and adhered to Bowman's capsule. Additional tubulo-interstitial lesions (not shown in Figure 2) included focal atrophy and fibrosis.


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)

Progressive glomerulosclerosis in podoCdc42−/− but not podoRac1−/− mice by light microscopy (PAS staining at 20× and 40× magnification). (A, B) Floxed control mice demonstrate normal tubulointerstitial and glomerular morphology at 3-4 weeks of age. (C, D) podoRac1−/− tubulointerstitial and glomerular morphology at 12 months of age is indistinguishable from control. Podocyte-specific loss of Cdc42 results in tubular protein casts and injury (E) as well as focal segmental glomerulosclerosis in a minority of glomeruli (F) at 3-4 weeks of age.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Progressive glomerulosclerosis in podoCdc42−/− but not podoRac1−/− mice by light microscopy (PAS staining at 20× and 40× magnification). (A, B) Floxed control mice demonstrate normal tubulointerstitial and glomerular morphology at 3-4 weeks of age. (C, D) podoRac1−/− tubulointerstitial and glomerular morphology at 12 months of age is indistinguishable from control. Podocyte-specific loss of Cdc42 results in tubular protein casts and injury (E) as well as focal segmental glomerulosclerosis in a minority of glomeruli (F) at 3-4 weeks of age.
Mentions: Kidney morphology at 4 weeks of age was examined by light microscopy (Figure 2). Compared to floxed Cdc42 or Rac1 controls (Figure 2, A and B), podoRac1−/− kidneys (Figure 2, C and D) showed no alteration in glomerular or tubulo-interstitial morphology for up to 12 months of age. In contrast, podoCdc42−/− mice displayed progressive focal and global glomerulosclerosis accompanied by diffuse tubular dilatation with protein casts and tubular injury (Figure 2, E and F). Podocytes often appeared prominent and vacuolated. Segmentally sclerotic portions contained abundant extracellular matrix and adhered to Bowman's capsule. Additional tubulo-interstitial lesions (not shown in Figure 2) included focal atrophy and fibrosis.

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