Abstract
Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell–cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.
Highlights
Glomerulopathies are the main reason for end-stage renal disease
Since Hippo signaling is known to be activated by a change of the rigidity of the extracellular matrix (ECM)[18], we examined the YAP localization in podocytes cultured on soft matrices with elastic moduli comparable to in vivo tissues (1–50 kPa; Fig. 1c)
Staining of cleaved caspase 3 revealed that the loss of nuclear YAP in podocytes cultured on very soft matrices (≤12 kPa) is accompanied with the induction of apoptotic processes (Fig. 1d)
Summary
Glomerulopathies are the main reason for end-stage renal disease. In most glomerulopathies, podocytes are directly or indirectly damaged[1]. Podocytes together with the glomerular basal membrane (GBM) and the endothelium form the blood-urine filtration barrier in the glomeruli of the kidney. With their large foot processes, interdigitating with the neighboring cells, they surround the glomerular capillaries in a tight cell layer, holding. Phosphorylation and activation of LATS 1/2 leads to phosphorylation of YAP and its paralog transcriptional co-activator with PDZ-binding motif (TAZ) Both are thereby excluded from the nucleus, affecting their ability to act as co-transcription factors for the transcription factor family of transcription enhancer factor TEF1-4, which influences the expression of a wide range of genes involved in cell proliferation, survival, and migration
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