Increased SGK1 activity potentiates mineralocorticoid/NaCl-induced kidney injury.

American journal of physiology. Renal physiology 2021 Apr 01

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Serum and glucocorticoid-regulated kinase 1 (SGK1) stimulates aldosterone-dependent renal Na+ reabsorption and modulates blood pressure. In addition, genetic ablation or pharmacological inhibition of SGK1 limits the development of kidney inflammation and fibrosis in response to excess mineralocorticoid signaling. In this work, we tested the hypothesis that a systemic increase in SGK1 activity would potentiate mineralocorticoid/salt-induced hypertension and kidney injury. To that end, we used a transgenic mouse model with increased SGK1 activity. Mineralocorticoid/salt-induced hypertension and kidney damage was induced by unilateral nephrectomy and treatment with deoxycorticosterone acetate and NaCl in the drinking water for 6 wk. Our results show that although SGK1 activation did not induce significantly higher blood pressure, it produced a mild increase in glomerular filtration rate, increased albuminuria, and exacerbated glomerular hypertrophy and fibrosis. Transcriptomic analysis showed that extracellular matrix- and immune response-related terms were enriched in the downregulated and upregulated genes, respectively, in transgenic mice. In conclusion, we propose that systemically increased SGK1 activity is a risk factor for the development of mineralocorticoid-dependent kidney injury in the context of low renal mass and independently of blood pressure.NEW & NOTEWORTHY Increased activity of the protein kinase serum and glucocorticoid-regulated kinase 1 may be a risk factor for accelerated renal damage. Serum and glucocorticoid-regulated kinase 1 expression could be a marker for the rapid progression toward chronic kidney disease and a potential therapeutic target to slow down the process.

Citation

Catalina Sierra-Ramos, Silvia Velazquez-Garcia, Ayse G Keskus, Arianna Vastola-Mascolo, Ana E Rodríguez-Rodríguez, Sergio Luis-Lima, Guadalberto Hernández, Juan F Navarro-González, Esteban Porrini, Ozlen Konu, Diego Alvarez de la Rosa. Increased SGK1 activity potentiates mineralocorticoid/NaCl-induced kidney injury. American journal of physiology. Renal physiology. 2021 Apr 01;320(4):F628-F643