KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression.

Autor:	Meliambro K; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Yang Y; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., de Cos M; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Rodriguez Ballestas E; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Malkin C; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Haydak J; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Lee JR; Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Salem F; Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA., Mariani LH; Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA., Gordon RE; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Basgen JM; Stereology and Morphometry Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA., Wen HH; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Fu J; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Azeloglu EU; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., He JC; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Wong JS; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Campbell KN; Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2023 Apr 10; Vol. 8 (7). Date of Electronic Publication: 2023 Apr 10.
DOI:	10.1172/jci.insight.165002
Abstrakt:	Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease.
Databáze:	MEDLINE
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