Wnt/β-Catenin Signaling Promotes Podocyte Dysfunction and Albuminuria

Abstract

Podocyte dysfunction, one of the major causes of proteinuria, leads to glomerulosclerosis and end stage renal disease, but its underlying mechanism remains poorly understood. Here we show that Wnt/␤-catenin signaling plays a critical role in podocyte injury and proteinuria. Treatment with adriamycin induced Wnt and activated ␤-catenin in mouse podocytes. Overexpression of Wnt1 in vivo activated glomerular ␤-catenin and aggravated albuminuria and adriamycin-induced suppression of nephrin expression, whereas blockade of Wnt signaling with Dickkopf-1 ameliorated podocyte lesions. Podocyte-specific knockout of ␤-catenin protected against development of albuminuria after injury. Moreover, pharmacologic activation of ␤-catenin induced albuminuria in wild-type mice but not in ␤-catenin-knockout littermates. In human proteinuric kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis, we observed upregulation of Wnt1 and active ␤-catenin in podocytes. Ectopic expression of either Wnt1 or stabilized ␤-catenin in vitro induced the transcription factor Snail and suppressed nephrin expression, leading to podocyte dysfunction. These results suggest that targeting hyperactive Wnt/␤-catenin signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.

Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development

“…This suggests a role of canonical Wnt signaling in the development of nephritis and, based on recent results for other glomerulopathies (9), provides a potential mechanism to explain the extracellular membrane expansion that accompanies progression toward proteinuria and renal failure. Previous work by our group revealed an increase in the glomerular expression of MMP-2 and MMP-9 during the development of lupus nephritis (25), which was accompanied by qualitative changes in the composition of the type IV collagen matrix of the glomerular basement membrane.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…Aberrant activation of these pathways has led to heart fibrosis, renal fibrosis, glomerulosclerosis, cystic disease and diabetic nephropathy. 6,112,[130][131][132][133] Overexpression of the (P)RR in the rat and mouse resulted in hypertension and fibrotic effects. 91,111,130 This raises several questions.…”

“…131,133 Impaired Wnt/PCP signaling is associated with abnormal kidney repair. 31 As noted above, (P)RR blockade inhibited the development and progression of glomerulosclerosis in Ang-II type 1a receptor-deficient diabetic mice, while RAS inhibitors only slowed the progression of diabetic nephropathy.…”

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

“…Зокрема, було показано, що експресія Wnt-лігандів підвищується в подоцитах як в експе-риментальній моделі, так і в матеріалі біопсій нирок пацієнтів із різними гломерулопатіями [8].…”

“…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].…”