Expression of Agrin, Dystroglycan, and Utrophin in Normal Renal Tissue and in Experimental Glomerulopathies

Raats, C.J.I.; Born, Jacob van den; Bakker, Marinka A.H.; Oppers‐Walgreen, Birgitte; Pisa, Brenda J.M.; Dijkman, Henry; Assmann, K.J.M.; Berden, Jo H. M.

doi:10.1016/s0002-9440(10)65046-8

Cited by 104 publications

(93 citation statements)

References 69 publications

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“…Actinin 4␣ is an actin-cross-linking protein, and mice with mutant actinin 4␣ revealed foot process fusion and podocyte vacuolization (31). DG1, a heavily glycosylated peripheral membrane protein located in podocytes, is thought to keep foot process shape, and it decreases in proteinuric renal diseases (32,44). Thus, the current study suggests that podocyte structure and function may already alter at an early stage of nephropathy.…”

Section: Discussionmentioning

confidence: 64%

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

et al. 2006

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Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1␣ (HIF-1␣), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4␣ and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4␣, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria. In addition, HIF-1␣ protein expression was partially attenuated by pioglitazone. These results suggest that not only metabolic alteration and oxidative stress, but also the alteration of gene expression related to glomerulogenesis and podocyte structure, may be involved in the pathogenesis of early diabetic glomerulopathy in type 2 diabetes. Diabetes

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Section: Discussionmentioning

confidence: 64%

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

et al. 2006

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“…The bends of the actin filament arches appear to be connected directly to the microtubules of the major processes (own unpublished results). FP are anchored to the GBM via ␣3␤1 integrin (5) and dystroglycans (6,7). Neighboring FP are connected by a cell-cell junction, the glomerular SD, which represents the main size selective filter barrier in the kidney (8 -10).…”

Section: Molecular Anatomy Of the Podocyte Fp Cytoskeletonmentioning

confidence: 99%

Podocyte Biology and Response to Injury

Mündel¹,

Shankland²

2002

Journal of the American Society of Nephrology

595

541

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The visceral glomerular epithelial cell, also called podocyte, is a terminally differentiated cell that lines the outer aspect of the glomerular basement membrane (GBM). It therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Indeed, all forms of nephrotic syndrome are characterized by abnormalities in the podocyte. In this review, we will provide an update of the known functions of recent podocyte-specific proteins and focus on the slit diaphragm (SD) and the mechanisms underlying foot process (FP) flattening and how the podocyte responds to injury. Molecular Anatomy of the Podocyte FP CytoskeletonPodocyte FP are not static, but rather contain a contractile system similar to that seen in pericytes. This contractile apparatus is composed of actin, myosin-II, ␣-actinin-4, talin, and vinculin (1). The actin filament bundles form arches between adjacent FP of the same podocyte (2). Figure 1 is a schema of our current understanding of the molecular composition of the cytoskeleton in podocyte FP. Importantly, the actin filaments are connected to the underlying GBM at focal contacts via an ␣3␤1 integrin complex (3,4). The bends of the actin filament arches appear to be connected directly to the microtubules of the major processes (own unpublished results). FP are anchored to the GBM via ␣3␤1 integrin (5) and dystroglycans (6,7). Neighboring FP are connected by a cell-cell junction, the glomerular SD, which represents the main size selective filter barrier in the kidney (8 -10). The SD is thought to be a modified adherens junction (11) that is composed of a growing number of proteins, including nephrin (12-14), P-cadherin, CD2AP (15-18), , FAT (20), podocin (16,21), and possibly Neph1 (see reference 22 and below). In addition to the contractile proteins described above, we have reported the association of synaptopodin with the actin filaments in FP (23). Synaptopodin is the first member of a novel class of prolinerich proteins (24) and, like ␣-actinin-4, interacts with the tight junction protein MAGI-1 (25) that is also expressed in podocytes (26). Four Major Causes of FP EffacementThe basolateral portion of the foot processes represents the center of podocyte function and is defined by three membrane domains: the apical membrane domain, the SD protein complex, and the basal membrane domain or sole plate (27). The submembranous regions of all compartments are connected to the FP actin cytoskeleton, e.g., on the apical membrane domain, podocalyxin associates with the actin cytoskeleton through interactions with ezrin and the actin cytoskeleton via Na ϩ /H ϩ -exchanger regulatory factor 2 (NHERF2), a scaffold protein containing two PDZ (PSD-95/Dlg/ZO-1) domains and an ERM-binding region (28,29). The FP actin cytoskeleton is highly dynamic and ultimately determines the structural maintenance of the filtration slits as demonstrated in the acute PS/heparin model by several groups (30 -32). Interference with one of the three domains eventually ...

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“…Podocyte FPs form a scaffolding around the capillary loops that are anchored to the glomerular basement membrane (GBM) via ␣ 3 ␤ 1 integrin (12) and ␣-/␤-dystroglycans (13,14). ␣ 3 ␤ 1 integrin represents a receptor for certain isoforms of laminin, including laminin-5 in the epidermal basement membrane and laminin-10/11 in the GBM (15).…”

mentioning

confidence: 99%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

162

135

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Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and ␣ 3 integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking ␣ 3 integrin. Similarly, acute functional inhibition of ␣ 3 integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of ␣ 3 integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and ␣ 3 integrin.Glomerular podocytes serve as a final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes and the interposed slit diaphragm (SD) 1 All forms of nephrotic syndrome are characterized by podocyte foot process (FP) effacement and/or molecular reorganization of the slit diaphragm (1). FP effacement requires a precise interplay of multiple cellular functions including structural alterations of the cytoskeleton, movement of FP over the basement membrane, and reconstruction of the slit diaphragm (1). The discovery of several novel podocyte proteins and their mutation analysis including nephrin (2), CD2AP (3), ␣-actinin-4 (4), podocin (5), neph1 (6), and FAT (7) have shed light on the pathogenesis of FP effacement and proteinuria and emphasized the critical role of podocyte FP and the SD in maintaining the function of the glomerular filtration barrier.

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Expression of Agrin, Dystroglycan, and Utrophin in Normal Renal Tissue and in Experimental Glomerulopathies

Cited by 104 publications

References 69 publications

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

Podocyte Biology and Response to Injury

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

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