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1.
FASEB J ; 32(2): 576-587, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28935820

RESUMEN

Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a downstream mediator of PI3K, which is essential for maintaining the functional integrity of podocytes. However, little is known about the role of SGK3 in podocyte function. Herein, we demonstrated that SGK3 contributes to the maintenance of podocyte integrity. Conditionally immortalized mouse podocyte cells (MPCs) were treated with puromycin aminonucleoside (PAN). PAN treatment inhibited the activity of SGK3 and the expression of podocin. Short hairpin RNA (shRNA)-mediated knockdown of SGK3 also reduced podocin expression in the absence of PAN. Adriamycin (ADR)-treated mice developed proteinuria and had decreased renal glomerular SGK3 expression in comparison to control mice. Consistent with a role for SGK3 in the ADR effect, SGK3 knockout (KO) mice had markedly reduced kidney podocin expression and significantly elevated proteinuria compared with wild-type mice. Electron microscopy revealed that SGK3 KO mice displayed partial effacement of podocyte foot processes. Further, a SGK3 target protein, glycogen synthase kinase-3 (GSK3), was discovered to be dramatically activated in PAN and SGK3 shRNA-treated MPCs and in SGK3 KO mice. Taken together, these data strongly suggest that SGK3 plays a significant role in regulating podocyte function, likely by controlling the expression and activity of GSK3.-Peng, L.-Q., Zhao, H., Liu, S., Yuan, Y.-P., Yuan, C.-Y., Mwamunyi, M.-J., Pearce, D., Yao, L.-J. Lack of serum- and glucocorticoid-inducible kinase 3 leads to podocyte dysfunction.


Asunto(s)
Podocitos/enzimología , Proteínas Serina-Treonina Quinasas/deficiencia , Animales , Línea Celular Transformada , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Podocitos/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Puromicina Aminonucleósido/efectos adversos , Puromicina Aminonucleósido/farmacología
2.
World J Clin Cases ; 7(16): 2393-2400, 2019 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-31531336

RESUMEN

BACKGROUND: Waldenström's macroglobulinemia (WM) is a rare lymphoid neoplasia, which can have renal complications. These rarely occur, and most common renal manifestations are mild proteinuria and microscopic hematuria. Herein we describe a case of WM that presented with pseudothrombi depositing in capillaries associated with minimal change nephrotic syndrome and chronic kidney disease (CKD). CASE SUMMARY: A 52-year-old man presented with features suggesting nephrotic syndrome. Extensive workups were done, and there were elevated serum levels of interleukin-6 and vascular endothelial growth factor (VEGF), capillary pseudothrombus accumulation associated with minimal change nephrotic syndrome, CKD, and WM. Treatment was directed at the patient's WM with bortezomib, thalidomide, and dexamethasone whereby serum immunoglobulin M (IgM) decreased. The damage of IgM on the kidney was corrected; thus, the patient's proteinuria and serum creatinine had improved. The patient is still under clinical follow-up. CONCLUSION: It is essential for clinicians to promptly pay more attention to patients presenting with features of nephrotic syndrome and do extensive workups to come up with a proper therapy strategy.

3.
Cell Death Dis ; 9(11): 1114, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30385740

RESUMEN

Podocyte damage is commonly accompanied by destabilization of the podocalyxin (PC)/ezrin complex. Serum- and glucocorticoid-inducible kinase 3 (SGK3) plays a role in the maintenance of podocyte function, but the details of this role are poorly understood. Herein we demonstrated that SGK3 and its downstream target protein neural precursor cell expressed developmentally downregulated protein 4 subtype 2 (Nedd4-2) triggered PC and ezrin interaction. In adriamycin (ADR)-induced nephritic mice, and after puromycin aminonucleoside (PAN)-induced podocyte damage in vitro, PC and ezrin protein expression levels decreased significantly, while Nedd4-2 activity increased. Moreover, PAN treatment increased PC and ezrin ubiquitination and decreased PC/ezrin interaction in cultured mouse podocytes. The downregulation of SGK3 activity in mouse podocytes resulted in decreased PC and ezrin protein expression and increased the ubiquitin-proteasome degradation of PC and ezrin. Furthermore, upregulation of SGK3 activity mostly reversed the PAN-induced decrease in PC and ezrin protein expression. Overexpression of Nedd4-2 led to decreased ezrin protein expression via the upregulation of ezrin ubiquitination. In contrast, Nedd4-2 knockdown resulted in increased ezrin protein expression but decreased ezrin ubiquitination. In PC-transfected human embryonic kidney (HEK293T) cells, SGK3 activity downregulation and Nedd4-2 overexpression resulted in decreased PC/ezrin interaction. These results suggested that SGK3 triggers the ubiquitin-proteasome degradation of PC and ezrin, while the SGK3/Nedd4-2 signaling pathway regulates ezrin, but not PC, ubiquitination. Thus SGK3 helps to regulate podocyte function by maintaining the stability of the PC/ezrin complex.


Asunto(s)
Proteínas del Citoesqueleto/genética , Nefritis/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/genética , Sialoglicoproteínas/genética , Animales , Línea Celular Transformada , Proteínas del Citoesqueleto/metabolismo , Doxorrubicina/toxicidad , Humanos , Masculino , Ratones , Ubiquitina-Proteína Ligasas Nedd4/genética , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Nefritis/inducido químicamente , Nefritis/genética , Nefritis/patología , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Estabilidad Proteica , Proteolisis , Sialoglicoproteínas/metabolismo , Transducción de Señal , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitinación/efectos de los fármacos
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