SIK1 localizes with nephrin in glomerular podocytes and its polymorphism predicts kidney injury.
Mutant α-adducin and endogenous ouabain levels exert a causal role in hypertension by affecting renal Na-K ATPase. In addition, mutant β-adducin is involved in glomerular damage through nephrin down-regulation. Recently, the salt-inducible kinase 1 (SIK1) has been shown to exert a permissive role on mutant α-adducin effects on renal Na-K ATPase activity involved in blood pressure (BP) regulation and a SIK1 rs3746951 polymorphism has been associated with changes in vascular Na-K ATPase activity and BP. Here, we addressed the role of SIK1 on nephrin and glomerular functional modifications induced by mutant β-adducin and ouabain, by using congenic substrains of the Milan rats expressing either mutant α- or β-adducin, alone or in combination, ouabain hypertensive rats (OHR) and hypertensive patients. SIK1 co-localized and co-immunoprecipitated with nephrin from glomerular podocytes and associated with caveolar nephrin signaling. In cultured podocytes, nephrin-gene silencing decreased SIK1 expression. In mutant β-adducin congenic rats and in OHR, the podocyte damage was associated with decreased nephrin and SIK1 expression. Conversely, when the effects of β-adducin on podocytes were blocked by the presence of mutant α-adducin, nephrin and SIK1 expressions were restored. Ouabain effects were also reproduced in cultured podocytes. In hypertensive patients, nephrinuria, but not albuminuria, was higher in carriers of mutant SIK1 rs3746951 than in wild-type, implying a more direct effect of SIK1 on glomerular damage. These results demonstrate that, through nephrin, SIK1 is involved in the glomerular effects of mutant adducin and ouabain and a direct effect of SIK1 is also likely to occur in humans.
Prassis Sigma-tau Research Institute, Via Forlanini, 3, Settimo Milanese, Milan, Italy, Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit mara.ferrandi@gmail.com.
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Ferrandi
Prassis Sigma-tau Research Institute, Via Forlanini, 3, Settimo Milanese, Milan, Italy, Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit.
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Molinari
Division of Genetics and Cell Biology, Biomolecular Mass Spectrometry Unit.
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Matafora
Division of Metabolic and Cardiovascular Sciences, Complications of Diabetes, and.
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Zerbini
Department of Internal and Specialistic Medicine, San Raffaele Scientific Institute, Milan, Italy.
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Trevisani
Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca Sulle Malattie Renali, Milan, Italy.
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Rastaldi
Department of Internal and Specialistic Medicine, San Raffaele Scientific Institute, Milan, Italy.
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Simonini
Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca Sulle Malattie Renali, Milan, Italy.
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Giardino
Prassis Sigma-tau Research Institute, Via Forlanini, 3, Settimo Milanese, Milan, Italy, CVie Therapeutics, Hong Kong, China and.
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Ferrari
Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit Università Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy.
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