Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes

Zhu, Jili; Sun, Ning-Zi; Aoudjit, Lamine; Li, H.; Kawachi, Hiroshi; Lemay, Serge Joseph Guy; Takano, Tomoko

doi:10.1038/sj.ki.5002691

Cited by 166 publications

(179 citation statements)

References 35 publications

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“…20 Reductions in nephrin phosphorylation, Nck/p85 binding, and Akt activation have also been detected in the puromycin aminonucleoside model of reversible podocyte injury 12,14,16,18 in parallel with increased expression of the phosphatase PTP1B, which can dephosphorylate nephrin Y1217. 58 By contrast, phosphorylation of nephrin on Y1176/Y1193 is increased with protamine sulfate as noted previously.…”

Section: Discussionmentioning

confidence: 99%

“…Within this segment, there exists a number of highly conserved tyrosine (Y) residues ( Table 1) that, on phosphorylation by Fyn kinase, [7][8][9] serve as docking sites for intracellular signaling proteins ( Figure 1A). 10 Through recruitment of actin adaptors, such as p85/PI3K, 11,12 the Cas/Crk complex, 13 and Nck1/2, 8,9,14 nephrin phosphorylation is postulated to facilitate direct and dynamic connection to the podocyte cytoskeleton. Moreover, Nck enhances nephrin phosphorylation via activation of Fyn, 15 and loss of Nck within podocytes leads to reduced nephrin tyrosine phosphorylation and widespread foot process effacement, 15,16 inferring a reciprocal relationship between Nck and nephrin in the maintenance of podocyte structure.…”

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confidence: 99%

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Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin Y3F/Y3F mice). Homozygous nephrin Y3F/Y3F mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin Y3F/Y3F mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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“…Treatment of diabetes mellitus through PI3K signaling pathway has recently been of great interest. PI3K simultaneously regulates Rac1 and Cdc42, which are associated with the actin cytoskeleton of kidney podocytes (Zhu et al, 2008). All PI3Ks are inhibited by the drugs wortmannin and LY294002.…”

Section: Introductionmentioning

confidence: 99%

The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats

et al. 2012

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Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to kidney glomeruli. Podocytes are glomerular epithelial cells and play critical roles in the glomerular filtration barrier. Recent studies have shown the importance of regulating the podocyte actin cytoskeleton in early DN. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, simultaneously regulates Rac1 and Cdc42, which destabilize the podocyte actin cytoskeleton during early DN. In this study, in order to evaluate the reno-protective effects of wortmannin in early DN by regulating Rac1 and Cdc42, streptozotocin (STZ)-induced proteinuric renal disease (SPRD) rats were treated with wortmannin. The albuminuria value of the SPRD group was 3.55 ± 0.56 mg/day, whereas wortmannin group was 1.77 ± 0.48 mg/day. Also, the albumin to creatinine ratio (ACR) value of the SPRD group was 53.08 ± 10.82 mg/g, whereas wortmannin group was 20.27 ± 6.41 mg/g. Changes in the expression level of nephrin, podocin and Rac1/Cdc42, which is related to actin cytoskeleton in podocytes, by wortmannin administration were confirmed by Western blotting. The expression levels of nephrin (79.66 ± 0.02), podocin (87.81 ± 0.03) and Rac1/Cdc42 (86.12 ± 0.02) in the wortmannin group were higher than the expression levels of nephrin (55.32 ± 0.03), podocin (53.40 ± 0.06) and Rac1/Cdc42 (54.05 ± 0.04) in the SPRD group. In addition, expression and localization of nephrin, podocin and desmin were confirmed by immunofluorescence. In summary, we found for the first time that wortmannin has a reno-protective effect on SPRD rats during the early DN. The beneficial effects of wortmannin in SPRD rats indicate that this compound could be used to delay the progression of the disease during the early DN stage.

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“…The recently proposed mechanosensitivity of TRPC6 channels 29 is not detectable at physiologically relevant pressures of Ͻ80 mmHg, 30 and three additional, independent studies failed to demonstrate that TRPC6 per se is mechanosensitive. [31][32][33] The second TRPC6-interacting protein, nephrin, is an essential constituent of the slit diaphragm contributing to actin reorganization in podocytes by engaging a phosphoinositide 3-kinase pathway 34 subsequent to phosphorylation by the Src family protein tyrosine kinase Fyn. 35 The functional relevance of TRPC6 phosphorylation by Fyn 36 was called into question on the basis of functional analyses of TRPC6 phosphorylation site mutants.…”

Section: Trpc6 and Podocyte Functionmentioning

confidence: 99%

Renal TRPathies

Dietrich¹,

Chubanov²,

Gudermann³

2010

Journal of the American Society of Nephrology

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One key function of the kidneys is the ultrafiltration of plasma by glomeruli to dispose of metabolic end products, excess electrolytes, and water. A vast array of ion channels and transporters are critical for filtration, secretion, and resorption of electrolytes to maintain homeostasis. In recent years, investigations have focused on several members of the large transient receptor potential (TRP) family of ion channels, because mutations in genes encoding members of three different TRP ion channel subfamilies have been linked to human kidney diseases. 1 Mutations in PKD1 (encoding TRPP1) and PKD2 (coding for TRPP2) occur at high frequency in individuals with autosomal dominant polycystic kidney disease. 2,3 The latter mutations and the pathophysiology of polycystic kidney disease are not discussed further in this overview because the topic has been covered by numerous insightful review articles. 4 -7 Missense and nonsense mutations in the gene coding for TRPC6 segregate with autosomal dominant FSGS, a kidney disease that leads to progressive renal failure. 8,9 Loss-of-function mutations in TRPM6 are also associated with hypomagnesemia with secondary hypocalcemia (HSH), a rare autosomal recessive disorder. 10 -12 The involvement of TRP channel mutations in hereditary kidney disease has shed new light on the molecular pathogenesis of renal failure and significantly enhanced our appreciation of the physiologic roles of TRP channels on tubular function. In this review, we focus exclusively on TRPC6 and TRPM6. TRPC6 AND PODOCYTE FUNCTIONTRPC6 is a nonselective cation channel and one of the seven members of the classical transient receptor potential (TRPC) family, which can be divided into subfamilies on the basis of amino acid similarity. Whereas TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approximately 64% amino acid identity. TRPC3, TRPC6, and TRPC7 form a structural and functional subfamily displaying 65 to 78% identity at the amino acid level and share a common activator, diacylglycerol (DAG). 13 DAG is produced by phospholipase C isozymes activated after agonist binding to appropriate receptors, such as the interaction of angiotensin II (AngII) with AT 1 receptors.Like all TRPC family members, TRPC6 harbors an invariant sequence, the TRP box (containing the amino acid sequence EWKFAR), in its C-terminal tail as well as three ankyrin repeats in the N-terminus (Figure 1, A and B). The predicted transmembrane topology is similar to that of other TRP channels with intracellular N-and C-termini, six membrane-spanning helices (S1 through S6), and a presumed pore-forming loop (P) between S5 and S6 (Figure 1, A and B). As deduced from Northern blot analyses, TRPC6 channels are most prominently expressed in lung tissues, 14 where they ABSTRACTMany ion channels and transporters are involved in the filtration, secretion, and resorption of electrolytes by the kidney. In recent years, the superfamily of transient receptor potential (TRP) ion channels have received deserved attention because mutated TRP ch...

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Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes

Cited by 166 publications

References 35 publications

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats

Renal TRPathies

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