Disease relevance of Nphs2

• Nphs2-/- mice developed proteinuria during the antenatal period and died a few days after birth from renal failure caused by massive mesangial sclerosis [1].
• We generated podocin-deficient (Nphs2-/-) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis [1].
• Podocyte-specific antigens, including WT-1, synaptopodin, nephrin, and podocin, were not expressed by any cells in glomerular crescents, suggesting that podocytes underwent profound phenotypic changes in this nephritis model [2].
• Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system [3].
• Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia [4].

High impact information on Nphs2

• Moreover, GST pull-down experiments reveal that podocin associates via its COOH-terminal domain with CD2AP, a cytoplasmic binding partner of nephrin, and with nephrin itself [5].
• Here we show, by immunoelectron microscopy, that podocin localizes to the podocyte foot process membrane, at the insertion site of the slit diaphragm [5].
• Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes [6].
• Like Nephrin and Podocin, Neph1 was enriched in Triton X-100 detergent-resistant membrane fractions [7].
• During the calcium switch, there were reversible changes in localization and detergent solubility of the slit diaphragm protein ZO-1 and alpha-actinin-4, whereas nephrin and podocin solubility were unchanged [8].

Chemical compound and disease context of Nphs2

• Nephrin and podocin are slit-diaphragm proteins identified in families with congenital nephrotic syndromes [9].

Biological context of Nphs2

• Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes [10].
• When crossed with another transgenic mice expressing Cre under the Podocin promoter (a podocyte specific gene), the intervening lacZ gene was removed activating the expression of Nef in podocytes [11].
• We determined that VEGF-A signaling regulates slit diaphragm proteins by inducing a dose-response podocin upregulation and increasing its interaction with CD2AP [12].
• Immunofluorescence staining, double-immunolabeling, confocal microscopy, semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and Western blotting were used to detect the distribution and expression of podocin, nephrin, alpha-actinin-4, and glyseraldehyde-3-phosphate dehydrogenase (GAPDH)/beta-actin [13].
• In this study, to investigate the molecular interactions among podocin, nephrin, and alpha-actinin-4, we reconstructed the RNA interference (RNAi) expression vector, pSilencer 2.1-U6, specifically targeting podocin mRNA, and it was transfected into the mouse podocyte clone (MPC5) [13].

Anatomical context of Nphs2

• On the cellular level--using immunostaining--we detected cells expressing podocin, nephrin and wt-1, characteristic for differentiated podocytes and other cells, which expressed Tamm-Horsfall protein, a marker for distal tubule epithelial cells of kidney tissue [14].

Associations of Nphs2 with chemical compounds

• CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties [9].

Regulatory relationships of Nphs2

• Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP [12].

Other interactions of Nphs2

• In relation to GAPDH, the mRNA reductions of podocin and nephrin were observed by about 65% and 70%, respectively [13].
• Effect of the knockdown of podocin mRNA on nephrin and alpha-actinin in mouse podocyte [13].

Analytical, diagnostic and therapeutic context of Nphs2

• Early glomerular filtration defect and severe renal disease in podocin-deficient mice [1].

References