Inducible Nephrin Transgene Expression in Podocytes Rescues Nephrin-Deficient Mice from Perinatal Death

Juhila, Juuso; Lassila, Markus; Roozendaal, Ramon; Lehtonen, Eero; Messing, Marcellinus Wilhelmus Johanne; Langer, Brigitte; Kerjaschki, Dontscho; Verbeek, J. Sjef; Holthöfer, Harry

doi:10.2353/ajpath.2010.080843

Cited by 22 publications

(17 citation statements)

References 42 publications

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“…Nephrin-KO mouse model confirmed the essential role of nephrin in SD structure and function [61,62]. NPHS1-KO or inducible mice showed podocyte effacement with proteinuria and early postnatal death, making it unsuitable for animal model of FSGS [63] (Table 2; Fig. 1).…”

Section: Nphs2 (Podocin) Modelmentioning

confidence: 83%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

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Section: Nphs2 (Podocin) Modelmentioning

confidence: 83%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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“…51 Beyond the kidney, nephrin is expressed and functional in several tissues, including the brain, testis, and pancreas. 48,52 However, nephrin Y3F/Y3F mice are fertile, and they do not display any overt changes in locomotor activity or coordination (data not shown), implying a unique requirement for nephrin phosphorylation in the mature podocyte.…”

Section: Discussionmentioning

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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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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“…9 In humans and mice with inherited nephrin deficiency due to loss-of-function mutations of NPHS1 10 or Nphs1 deletion (Nphs1 2/2 ), 7,8 massive proteinuria develops in utero or soon after birth. A series of elegant studies from the laboratories of Holzman,11,12 Quaggin, 13 and Holthofer 14,15 highlighted the function of nephrin in rodents. In humans, nephrin is downregulated in many forms of acquired glomerular diseases, such as diabetic nephropathy, [16][17][18][19] minimal-change disease, [20][21][22] FSGS, 23 and membranous nephropathy, 21,23,24 and others.…”

mentioning

confidence: 99%

Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys

Chuang

D’Agati

et al. 2015

Journal of the American Society of Nephrology

105

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Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference-mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm-mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm-mediated signaling to preserve glomerular function and podocyte viability in adult mice.

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Inducible Nephrin Transgene Expression in Podocytes Rescues Nephrin-Deficient Mice from Perinatal Death

Cited by 22 publications

References 42 publications

Recent advances of animal model of focal segmental glomerulosclerosis

Recent advances of animal model of focal segmental glomerulosclerosis

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

Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys

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