Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Abstract

Diabetic kidney disease (DKD) is the single most common cause of albuminuria and end-stage kidney disease in the UnitedStates. We found increased expression of Wnt/␤-catenin (Ctnnb1) pathway transcripts and proteins in glomeruli and podocytes of patients and mouse models of DKD. Mice with podocyte-specific expression of stabilized Ctnnb1 exhibited basement membrane abnormalities, albuminuria, and increased susceptibility to glomerular injury. Mice with podocyte-specific deletion of Ctnnb1 or podocyte-specific expression of the canonical Wnt inhibitor Dickkopf-related protein 1 (Dkk1) also showed increased susceptibility to DKD. Podocytes with stabilized Ctnnb1 were less motile and less adhesive to different matrices. Deletion of Ctnnb1 in cultured podocytes increased the expression of podocyte differentiation markers and enhanced cell motility; however, these cells were more susceptible to apoptosis. These results indicate that Wnt/Ctnnb1 signaling in podocytes plays a critical role in integrating cell adhesion, motility, cell death, and differentiation. Balanced Ctnnb1 expression is critical for glomerular filtration barrier maintenance. Diabetic kidney disease (DKD)2 is one of the most devastating complications of diabetes and the single most common cause of albuminuria, chronic kidney disease, and end-stage renal disease (ESRD) in the Western world (1). DKD causes filtration unit dysfunction leading to the development of albuminuria, which is the most abundant protein component of the blood. The glomerular filtration barrier consists of three layers as follows: glomerular endothelial cells, the glomerular basement membrane (GBM), and the glomerular epithelial cell (or podocyte) layer (2-4). Decreased glomerular podocyte density is shown to be the strongest predictor for end-stage renal disease development in patients with diabetes (5). Hyperglycemia via the generation of reactive oxygen species induces podocyte apoptosis and loss, which has been well documented in many different mouse DKD models (6, 7). As podocytes are terminally differentiated cells, they are unable to proliferate; therefore, apoptosis or detachment can lead to podocyte deficiency, which in turn will lead to glomerulosclerosis development (8, 9). Early administration of drugs that prevent podocyte apoptosis has been shown to ameliorate DKD in rodent models; however, this may not be a clinically translatable strategy (6, 10). Another early lesion in diabetes is the thickening of the basement membrane. The role and mechanism of GBM thickening are not fully understood. It is speculated that GBM thickening could cause alterations in integrin expression, which could interfere with podocyte adhesiveness. Genetic deletion of podocyte-specific integrins, Itgb1 and Itga3, causes albuminuria and glomerulosclerosis; however, the contribution of podocyte adhesion to DKD development has not been demonstrated (11,12). Understanding the mechanism of podocyte differentiation, adhesion and cell death could be highly relevant for the development of targets f...

Podocyte Mitosis – A Catastrophe

“…Tracing nephrogenesis in embryonic conditional β -catenin knockout mice revealed that these “parietal podocytes” derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. It has been also reported that increased Wnt expression was associated with loss of podocyte differentiation markers and expression of parietal cell type-specific markers, whereas deletion of Ctnnb1 increased the expression of podocyte markers [112]. However, it is possible that the renal effects of systemic manipulation of signaling pathways, such as Notch and Wnt, are highly context- and probably disease-dependent.…”

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

“…[7][8][9][10] As a transcriptional regulator, b-catenin is translocated into the nucleus on stimulation, wherein it binds to members of the T cell factor (TCF)/lymphoid enhancerbinding factor family of transcription factors. Nuclear b-catenin/TCF then assembles a transcriptionally active complex by recruiting transcriptional coactivators, such as the cAMP response element-binding protein-binding protein (CBP), to stimulate the transcription of its target genes.…”

Циліопатії, роль Wnt-сигнального шляху в перебігу гострого (постінфекційного) гломерулонефриту: огляд літератури та власне спостереження

“…Також у моделях діабетичної нефропатії відзначалося підвищення гломерулярної експресії Wnt1, Wnt2b, Wnt4, Wnt6, Wnt16. Тож під-вищення експресії Wnt-лігандів характерне для люд-ських та тваринних моделей гломерулопатій [9].…”

“…Усі миші виявилися здоровими, що вказує на відсутність впливу даного Wnt-/-катенін-сигнального шляху на подоцити, однак результати усіх досліджень вказують на шкід-ливий вплив активності -катеніну саме під час го-строго та хронічного гломерулярного ушкодження, включаючи модель діабетичної нефропатії. Крім того, в іншому експерименті було показано, що інгі-бітор Wnt-сигнального шляху, який діє на корецеп-тор LRP5/6, зменшує гломерулярне ушкодження [8][9][10].…”