Positionally Cloned Gene for a Novel Glomerular Protein—Nephrin—Is Mutated in Congenital Nephrotic Syndrome

Kestilä, Marjo; Lenkkeri, Ulla; Männikkö, Minna; Lamerdin, Jane E.; McCready, Paula; Putaala, Heli; Ruotsalainen, Vesa; Morita, Takako; Nissinen, Marja; Herva, Riitta; Kashtan, Clifford E.; Peltonen, Leena; Holmberg, Christer; Olsen, Anne S.; Tryggvason, Karl

doi:10.1016/s1097-2765(00)80057-x

Cited by 1,686 publications

(1,438 citation statements)

References 33 publications

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“…Postnatal inactivation of podocin in mature kidneys by elective Cre induction led to massive proteinuria, glomerulosclerosis, and death in renal failure within a median of 11 weeks [59]. Nephrin (encoded by the NPHS1 gene) was identified as the cause of disease in congenital NS of the Finnish type [60]. Nephrin-KO mouse model confirmed the essential role of nephrin in SD structure and function [61,62].…”

Section: Nphs2 (Podocin) Modelmentioning

confidence: 88%

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: 88%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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“…The importance of podocytes in maintaining the integrity of the glomerular filtration barrier was encapsulated by the discovery of the key podocyte protein, nephrin, in 1998. Mutations in NPHS1, which encodes nephrin, result in congenital nephrotic syndrome of the Finnish type [34]. Since the discovery of nephrin, a number of genes have been found to be mutated in human nephrotic syndromes or animal models and these discoveries have provided significant insights into disease mechanisms [35].…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

et al. 2009

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Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR) γ agonists are used increasingly in the treatment of type 2 diabetes. In the context of renal disease, PPARγ agonists reduce microalbuminuria in diabetic nephropathy; however, the mechanisms underlying this effect are unknown. Glomerular podocytes are newly characterised insulin-sensitive cells and there is good evidence that they are targeted in diabetic nephropathy. In this study we investigated the functional and molecular effects of the PPARγ agonist rosiglitazone on human podocytes. Methods Conditionally immortalised human podocytes were cultured with rosiglitazone and functional effects were measured with glucose-uptake assays. The effect of rosiglitazone on glucose uptake was also measured in 3T3-L1 adipocytes, nephrin-deficient podocytes, human glomerular endothelial cells, proximal tubular cells and podocytes treated with the NEFA palmitate. The role of the glucose transporter GLUT1 was investigated with immunofluorescence and small interfering RNA knockdown and the plasma membrane expression of GLUT1 was determined with bis-mannose photolabelling. Results Rosiglitazone significantly increased glucose uptake in wild-type podocytes and this was associated with translocation of GLUT1 to the plasma membrane. This effect was blocked with GLUT1 small interfering RNA. Nephrin-deficient podocytes, glomerular endothelial cells and proximal tubular cells did not increase glucose uptake in response to either insulin or rosiglitazone. Furthermore, rosiglitazone significantly increased basal and insulinstimulated glucose uptake when podocytes were treated with the NEFA palmitate. Conclusions/interpretation In conclusion, rosiglitazone has a direct and protective effect on glucose uptake in wild-type human podocytes. This represents a novel mechanism by which PPARγ agonists may improve podocyte function in diabetic nephropathy.

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“…Mutations in the genes encoding nephrin and podocin were the first to be identified causing inherited isolated nephrotic syndrome (NS) [26, 27], representing the major genetic cause of congenital and infantile NS, respectively. The indispensable role of nephrin ( NPHS1 ) at the slit diaphragm was shown further by the development of NPHS1 -null mice, which displayed massive proteinuria and died within 24 h of birth [28].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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Positionally Cloned Gene for a Novel Glomerular Protein—Nephrin—Is Mutated in Congenital Nephrotic Syndrome

Cited by 1,686 publications

References 33 publications

Recent advances of animal model of focal segmental glomerulosclerosis

Recent advances of animal model of focal segmental glomerulosclerosis

Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1

Podocyte Mitosis – A Catastrophe

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