Repair problems in podocytes: Wnt, Notch, and glomerulosclerosis

Abstract

Wnt/Ctnnb1 and Notch signaling play key roles in kidney development and epithelial cell specification. Recent reports have suggested that these pathways are reactivated in response to injury and in different disease conditions. Studies using genetically modified animal models showed that sustained activation of Notch and Wnt signaling in podocytes are causally related to albuminuria and glomerulosclerosis development. Here, we discuss the role and regulation of Wnt/Ctnnb1 and Notch signaling in podocytes.

Figure 1. Comparing and contrasting regeneration and repair in different species and organs

A. In the hydra, amputation causes apoptosis and caspase activation, which is the signal for regeneration. Activation of the Wnt, Hh pathways induce cell proliferation and complete regeneration of organs. B. In the liver partial hepatectomy induces a caspase activation and Wnt and Notch mediated repair of the organ. C. Nephron removal in zebrafish prompts the growth of new nephrons and regeneration of kidney. D. New nephrons are not formed in mice and partial nephrectomy causes remaining cells to enlarge and tubular cells to proliferate and functional repair occurs. E. More than 20% podocyte loss causes sustained albuminuria and structural damage. Enhanced Notch and Wnt signaling in podocytes cause further damage, cellular dedifferentiation, apoptosis, causing glomerulosclerosis and functional deterioration of the kidney.

Figure 2. Podocyte injury causing further podocyte injury via activation of repair pathways

Genetic mutations or environmental stressors (for example hyperglycemia, hypertension) cause podocyte stress. Podocyte stress activates a local vicious cycle causing the release of different damaging cytokines for example transforming growth factor beta and angiotensin. These pathways not only cause podocyte damage but they activate local repair pathways including Wnt/Ctnnb1 and Notch. Wnt/Ctnnb1 signaling induces podocyte dedifferention and detachment. Enhanced Notch activity can elicit further podocyte apoptosis. Both podocyte detachement and apoptosis lead to further podocyte loss, in turn decreasing VEGF levels, inducing capillary collapse and ultimately glomerulosclerosis. The cycle continues as podocyte loss will cause further stress to remaining podocytes and sustained activation of repair pathways ultimately causing the damage of the glomerulus. Red arrows denote potential therapeutic interventions: blocking TGFb or angiotensin action or by limiting the activation of repair pathways Wnt and Notch we can break the vicious cycle and halt glomerulosclerosis development.

Figure 3. Role of Notch and Wnt/Ctnnb1 in podocyte development and disease

Schematic representation of the activation of the Notch and the Wnt/Ctnnb1 pathways in podocytes. Expression of the ligand (Delta of Jagged family) on the ligand expressing cell induces proteolytic cleavage of the Notch receptor on the signal receiving cell, releasing the Notch intracellular domain (NICD). NICD travels to the nucleus and binds to other transcriptional regulators including Rbpj and regulates gene transcription. Binding of the Wnt ligand to its receptor (Lrp5/6 and Frizzled) causes the inhibition of the Ctnnb1 destruction complex, thereby stabilizing Ctnnb1. Ctnnb1 then travels to the nucleus, binds to other transcriptional regulators including proteins from the Tcf family and thereby regulate gene transcription. During development high Wnt/Ctnnb1 and Notch activity is necessary for podocyte development. Once development is complete both pathways are mainly silenced in adult podocytes. Reactivation of Notch and Wnt/Ctnnb1 can be observed in the context of albuminuria and glomerular disease. Increased Notch and Ctnnb1 activities contribute to proteinuria and glomerulosclerosis development.