Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin

Topham, Peter; Kawachi, Hiroshi; Haydar, Samir; Chugh, Sumant S.; Addona, Theresa A.; Charron, Kathryn B.; Holzman, Lawrence B.; Shia, Michael A.; Shimizu, Fujio; Salant, David J.

doi:10.1172/jci7728

Cited by 158 publications

(107 citation statements)

References 15 publications

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“…Proteinuria may occur with apparently normal looking slit diaphragm, as is the case in some NPHS1 patients with minor mutations (14). Also, when anti-nephrin antibodies are injected into rats, proteinuria appears in a few hours but the electron microscopic findings remain quite normal (19,20). Moreover, three of the eight MCNS patients in our study had reached remission 4 -7 d before the renal biopsies and still showed slit pores without the linear image of slit diaphragm.…”

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confidence: 50%

The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

et al. 2002

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The pathophysiology of proteinuria in acquired kidney diseases is mostly unknown. Recent findings in genetic renal diseases suggest that glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play an important role in the development of proteinuria. In this work we systematically evaluated the podocyte slit pores by transmission electron microscopy in two important nephrotic diseases, minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN). As controls, we used kidneys with tubulointerstitial nephritis (TIN). Effacement of podocyte foot processes was evident in proteinuric kidneys. However, quite normal looking foot processes and slit pores with varying width were also observed. Careful analysis of slit pores revealed, that the proportion of the pores spanned by the linear image of slit diaphragm, was reduced by 39% in kidneys from MCNS patients (1265 pores analyzed) compared with TIN samples (902 pores analyzed, p ϭ 0.0003). To enhance the detection rate of the slit diaphragms, the "empty" podocyte pores were further analyzed with tilting series from Ϫ45 to ϩ45. This revealed the linear diaphragm image in 71% and 26% of the slits in TIN and MCNS kidneys, respectively (p ϭ 0.0003). In contrast to findings in MCNS, no significant reduction of the slit diaphragms were seen in MN kidneys compared with the controls. The results suggest that MCNS is associated with disruption of glomerular slit diaphragms. The primary urine in the kidney forms by ultrafiltration of plasma components through the glomerular capillary wall into the urinary space (1). This glomerular filtration barrier is composed of a fenestrated endothelium, glomerular basement membrane (GBM) and epithelial cell (podocyte) layer. The podocyte layer consist intercalated foot processes, which are connected by 35-45 nm wide extracellular structure, termed the slit diaphragm. Normally, water and small plasma solutes filtrate easily through this sieve but the passage of proteins with the size of albumin and larger is almost completely restricted. The GBM has been thought to be the most important component in this size and charge selective sieving, and defects in the GBM have been regarded responsible for proteinuria in many glomerular diseases (2). Recent findings, however, have challenged the central role of the GBM in nephrotic diseases (3,4).Proteinuria is constantly associated with an effacement of podocyte foot processes, which has generally been regarded as a secondary phenomenon (5). Recent discoveries in the genetic diseases, however, suggest that podocytes may play a primary role in the development of proteinuria (6, 7). Mutations in NPHS1 gene coding for a podocyte specific protein, nephrin, are responsible for the congenital nephrotic syndrome of the Finnish type (NPHS1) (8, 9). Similarly, mutations in NPHS2 gene coding for another podocyte protein, podocin, are associated with a hereditary form of focal segmental glomerulosclerosis (FSGS) (10). Nephrin and podocin both localize at t...

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The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

et al. 2002

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“…Six nephrin antibodies were used: anti-nephrin 5-1-6 IgG, a mouse monoclonal antibody (mAb) against the extracellular domain of nephrin 26 (obtained from Dr. Fujio Shimizu, Niigata University, Niigata, Japan); mouse mAb anti-nephrin 043 raised against the extracellular domain of rat nephrin (amino acids 749 to 1030); and four rabbit polyclonal antibodies, including protein A-purified (Amersham Biosciences) anti-nephrin 1109, raised against human nephrin, 27 anti-nephrin 029, raised against the cytoplasmic tail of rat nephrin, 27 anti-nephrin 1054, raised against the cytoplasmic tail of human nephrin, 24 and anti-nephrin (LH) raised against the cytoplasmic tail of mouse nephrin 3 (obtained from Dr. Lawrence Holzman, University of Michigan, Ann Arbor, MI). Rabbit anti-CD2AP R209 was raised against amino acids 331 to 637 of mouse CD2AP, and anti-CD2AP 1774 was raised against mouse CD2AP as described.…”

Section: Antibodiesmentioning

confidence: 99%

Nephrin Forms a Complex with Adherens Junction Proteins and CASK in Podocytes and in Madin-Darby Canine Kidney Cells Expressing Nephrin

Lehtonen

Kudlicka

Holthöfer

et al. 2004

The American Journal of Pathology

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“…Perturbation of nephrin results in massive proteinuria with the effacement of the foot processes (15,16). The expression level of nephrin decreases in PAN nephrosis rats (17,18).…”

Section: Expression Levels Of Nephrin and Midkine In Glomeruli Of Panmentioning

confidence: 99%

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Suzuki¹,

Ito²,

Imai³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases.

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Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin

Cited by 158 publications

References 15 publications

The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

Nephrin Forms a Complex with Adherens Junction Proteins and CASK in Podocytes and in Madin-Darby Canine Kidney Cells Expressing Nephrin

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

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