Nuclear YAP localization as a key regulator of podocyte function

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.

Nuclear exclusion of YAP exacerbates podocyte apoptosis and disease progression in Adriamycin-induced focal segmental glomerulosclerosis

“…Whether podocyte injury leads to YAP nuclear exclusion, or YAP nuclear exclusion promotes podocyte injury in vivo, is still a problem to be explored [32]. In the present study, we found accumulation of nuclear YAP in podocytes in MCD with little podocyte apoptosis.…”

Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy

“…YAP signalling is involved in the pathogenesis of cystic nephropathy and is up-regulated in fibroblasts to increase the synthesis of the extracellular matrix and to promote renal fibrosis 35 . A comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database found that focal segmental glomerulopathy is also associated with an activation of the Hippo pathway in podocytes 36 . Further studies have found that the loss of YAP in podocytes leads to podocyte apoptosis 37,38 .…”

“…At present, most studies on YAP in podocytes suggest that the activation of YAP signalling has a protective effect on podocytes. Podocyte-specific YAP knockout can lead to the loss of foot processes, impaired renal function, and proteinuria 36,40 . In the present study, we found that the expression of desmin and snail2 significantly increased in podocytes overexpressing YAP, while expression of the podocyte cytoskeleton-associated protein, synaptopodin, significantly decreased after YAP overexpression/ Therefore, we propose that the activation of YAP signalling may have promoted podocyte re-entry into the cell cycle, leading to changes in the cytoskeleton and podocyte dedifferentiation.…”

Differentiating Staphylococcus infection-associated glomerulonephritis and primary IgA nephropathy: a mass spectrometry-based exploratory study

“…These changes may be the cause or effect of increased podocyte injury in SAGN glomeruli, and may facilitate the often encountered nephrotic-range proteinuria in SAGN. The Hippo www.nature.com/scientificreports/ pathway, also predicted to be activated in SAGN glomeruli may result in podocyte damage [27][28][29] , and contribute to the nephrotic range proteinuria. The tubulointerstitial proteome of SAGN showed significantly higher expression of TGM2, compared to IgAN, also shown by IHC staining.…”

“…These changes may be the cause or effect of increased podocyte injury in SAGN glomeruli, and may facilitate the often encountered nephrotic-range proteinuria in SAGN. The Hippo pathway, also predicted to be activated in SAGN glomeruli may result in podocyte damage 27 – 29 , and contribute to the nephrotic range proteinuria.…”