Mdm4 controls ureteric bud branching via regulation of p53 activity
MECHANISMS OF DEVELOPMENT
Authors: Hilliard, Sylvia A.; Li, Yuwen; Dixon, Angelina; El-Dahr, Samir S.
The antagonism between Mdm2 and its close homolog Mdm4 (also known as MdmX) and p53 is vital for embryogenesis and organogenesis. Previously, we demonstrated that targeted disruption of Mdm2 in the Hoxb7 + ureteric bud (Ub) lineage, which gives rise to the renal collecting system, causes renal hypodysplasia culminating in perinatal lethality. In this study, we examine the unique role of Mdm4 in establishing the collecting duct system of the murine kidney. Hoxb7Cre driven loss of Mdm4 in the Ub lineage (Ub(Mdm4-/-)) disrupts branching morphogenesis and triggers UB cell apoptosis. Ub(Mdm4-/-) kidneys exhibit abnormally dilated Ub tips while the medulla is hypoplastic. These structural alterations result in secondary depletion of nephron progenitors and nascent nephrons. As a result, newborn Ub(Mdm4-/-) mice have hypo-dysplastic kidneys. Transcriptional profiling revealed downregulation of the Ret-tyrosine kinase pathway components, Gdnf, Wnt11, Sox8, Etv4 and Cxcr4 in the Ub(Mdm4-/-) mice relative to controls. Moreover, the expression levels of the canonical Wnt signaling members Axin2 and Wnt9b are downregulated. Mdrn4 deletion upregulated p53 activity and p53-target gene expression including Cdkn1 alpha (p21), Gdf15, Ccng1, PERP, and Fas. Germline loss of p53 in Ub(Mdm4-/-) mice largely rescues kidney development and terminal differentiation of the collecting duct. We conclude that Mdm4 plays a unique and vital role in Ub branching morphogenesis and collecting system development.
HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model
JOURNAL OF PHARMACOLOGICAL SCIENCES
Authors: Irie, Yuhei; Tsubota, Maho; Maeda, Mariko; Hiramoto, Shiori; Sekiguchi, Fumiko; Ishikura, Hiroyasu; Wake, Hidenori; Nishibori, Masahiro; Kawabata, Atsufumi
HMGBI, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/ allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alpha capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.