Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases

Kang

Molecular Nutrition Food Res

et al. 2019

Scope Podocytes are a component of glomerular filtration barrier with interdigitating foot processes. The podocyte function depends on the dynamics of actin cytoskeletal and focal adhesion crucial for foot process structure. This study investigates the renoprotective effects of eucalyptol on the F‐actin cytoskeleton formation and focal adhesion assembly in glucose‐loaded podocytes and diabetic kidneys. Methods and results Eucalyptol at 1–20 µm reverses the reduction of cellular level of F‐actin, ezrin, cortactin, and Arp2/3 in 33 mm glucose‐loaded mouse podocytes, and oral administration of 10 mg kg–1 eucalyptol elevates tissue levels of actin cytoskeletal proteins reduced in db/db mouse kidneys. Eucalyptol inhibits podocyte morphological changes, showing F‐actin cytoskeleton formation in cortical regions and agminated F‐actin along the cell periphery. Eucalyptol induces focal adhesion proteins of paxillin, vinculin, talin1, FAK, and Src in glucose‐exposed podocytes and diabetic kidneys. Additionally, GTP‐binding Rac1, Cdc42, Rho A, and ROCK are upregulated in glucose‐stimulated podocytes and diabetic kidneys, which is attenuated by supplying eucalyptol. Rho A gene depletion partially diminishes GSK3β induction of podocytes by glucose. Conclusion Eucalyptol ameliorates F‐actin cytoskeleton formation and focal adhesion assembly through blockade of the Rho signaling pathway, entailing partial involvement of GSK3β, which may inhibit barrier dysfunction of podocytes and resultant proteinuria.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Eucalyptol Ameliorates Dysfunction of Actin Cytoskeleton Formation and Focal Adhesion Assembly in Glucose‐Loaded Podocytes and Diabetic Kidney

Kang

Molecular Nutrition Food Res

et al. 2019

Journal Cellular Physiology

Effects of heparin and derivatives on podocytes: An in vitro functional and morphological evaluation

Delézay

Hé

Sabido

et al. 2019

Unfractionated heparin (UFH) and low molecular heparin derivatives (LMWH) display numerous biological properties in addition to their anticoagulant effects. However, due to the physicochemical heterogeneity of these drugs, a better understanding concerning their effects on human cells is clearly needed. Considering that heparins are mainly excreted by the kidney, we focused our attention on the effect of UFH and LMWH on human podocytes by functional and morphological/phenotypic in vitro analyses. We demonstrated that these products differentially modulate the permeability of podocyte monolayer to albumin. The functional perturbations observed were correlated to significant cellular morphological and cytoskeletal changes, as well as a decrease in the expression of proteins involved in podocyte adherence to the extracellular matrix or intercellular interactions. This point confirms that UFH and the different LMWHs exert specific effects on podocyte permeability and underlines the need of in vitro tests to evaluate new biological nonanticoagulant properties of LMWH.

The Journal of Pathology

Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity

Fédou

Camus

Lescat

et al. 2021

Congenital anomalies of the kidney and the urinary tract (CAKUT) are the first cause of chronic kidney disease in childhood. Several genetic and environmental origins are associated with CAKUT, but most pathogenic pathways remain elusive. Considering the amniotic fluid (AF) composition as a proxy for fetal kidney development, we analyzed the AF proteome from non-severe CAKUT (n = 19), severe CAKUT (n = 14), and healthy control (n = 22) fetuses using LC-MS/MS. We identified 471 significant proteins that discriminated the three AF groups with 81% precision. Among them, eight proteins independent of gestational age (CSPG4, LMAN2, ENDOD1, ANGPTL2, PRSS8, NGFR, ROBO4, PLS3) were associated with both the presence and the severity of CAKUT. Among those, five were part of a protein-protein interaction network involving proteins previously identified as being potentially associated with CAKUT. The actin-bundling protein PLS3 (plastin 3) was the only protein displaying a gradually increased AF abundance from control, via non-severe, to severe CAKUT. Immunohistochemistry experiments showed that PLS3 was expressed in the human fetal as well as in both the fetal and the postnatal mouse kidney. In zebrafish embryos, depletion of PLS3 led to a general disruption of embryonic growth including reduced pronephros development. In postnatal Pls3-knockout mice, kidneys were macroscopically normal, but the glomerular ultrastructure showed thickening of the basement membrane and fusion of podocyte foot processes. These structural changes were associated with albuminuria and decreased expression of podocyte markers including Wilms' tumor-1 protein, nephrin, and podocalyxin. In conclusion, we provide the first map of the CAKUT AF proteome that will serve as a reference for future studies. Among the proteins strongly associated with CAKUT, PLS3 did surprisingly not specifically affect nephrogenesis but was found as a new contributor in the maintenance of normal kidney function, at least in part through the control of glomerular integrity.