Hippo signaling in the kidney: the good and the bad

Abstract

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

Keywords: Hippo; kidney; podocyte.

Fig. 1.

Hippo-mutant phenotypes in Drosophila and mice. Electron micrographs of wild-type (A) and homozygous mutant Hippo (Hpo) gene (B) are shown. C: mouse liver from a wild-type animal at 2 mo of age. D: mouse liver from a Mst1^−/−Mst2^−/− conditional knockout animal. This image was reproduced from Ref. with permission (Company of Biologists, Ltd., 2011).

Fig. 2.

Dysregulation of the mammalian Hippo pathway leads to tumorigenesis in vivo. A: liver from an ApoE/rtTA-YAP mouse raised on Dox for 8 wk, starting at 3 wk after birth. Note the presence of discrete nodules scattered throughout the liver (arrowheads). B: liver from an ApoE/rtTA-YAP mouse raised on Dox for 3 mo, starting at birth. Note the widespread development of hepatocellular carcinoma throughout the liver. This image was reproduced from Ref. with permission (Elsevier, 2012).

Fig. 3.

The core Hippo pathway. KIBRA/NF2 promote phosphorylation and activation of MST 1/2 and Sav1. This in turn phosphorylates and activates LATS1/2 and MOB1. LATS 1/2 phosphorylates YAP/TAZ, leading to its cytoplasmic sequestration, inactivation, and degradation. When YAP/TAZ are dephosphorylated, they enter the nucleus to induce gene transcription by interacting with TEAD1-4 transcription factors.

Fig. 4.

Periodic acid-Schiff (PAS) stainings of Yap-knockout (KO) and control (Ctrl) mice at 12 wk. A and B: Ctrl kidney sections at low and high power. C: Yap-KO mice with focal glomerulosclerosis and tubular dilatation and casts. D: Yap-KO mouse with a lesion of focal segmental glomerulosclerosis. This image was reproduced from Ref. with permission (American Society of Nephrology, 2016).