Chronic kidney disease‐induced insulin resistance is mediated by increased phosphorylation of SGK1 and enhanced SGLT2 expression in NTS

Abstract

BackgroundThe serum and glucocorticoid inducible‐kinase‐1 (SGK1) expression is regulated during discrete developmental stages and pathological conditions, such as hypertension and diabetic neuropathy. In the present study, chronic kidney disease (CKD) in rats enhanced SGK1 function and regulation within the nucleus tractus solitarii (NTS). This study aimed to assess the regulatory mechanism of SGK1 in the NTS in rats presenting CKD‐induced insulin resistance.MethodsEight‐week‐ and nine‐week‐old male Wistar–Kyoto (WKY) rats underwent nephrectomy of the left and right kidneys, respectively. After subjecting the rats to CKD‐induced hypertension for 2 weeks, they were treated with SGK1 inhibitor (GSK650394, 100 mM) for another 2 weeks. Furthermore, the rats underwent 5/6 nephrectomy for 4 weeks; thereafter, they were tested for blood pressure, blood and urine chemistry, renal function, and protein expression. Mann–Whitney U test was used to compare the mean rank differences in scales of the general parameters between the CKD (sham, CKD, and CKD + GSK650394) groups, and the values were presented as mean ± SEM.ResultsRats with CKD revealed proteinuria, lower urine sodium and chloride levels and hyperglycemia, while treatment with SGK1 inhibitor significantly decreased these effects. Immunoblotting analysis further revealed that phospho‐SGK1 (Ser78), phosphoinositide‐dependent kinase‐1 (PDK1), and sodium‐glucose co‐transporter 2 (SGLT2) expressions increased in the NTS of CKD rats. Furthermore, inhibition of phospho‐SGK1 (Ser78) by GSK650394 significantly decreased the expression of PDK1 and SGLT2 in the NTS of CKD rats.ConclusionOur results suggest that inhibition of SGK1 expression in the NTS by intracerebroventricularly injected SGK1 inhibitor decreases the fasting serum glucose by negatively regulating CKD‐induced SGK1 signaling, reducing SGK1 (Ser78) phosphorylation, and by inhibiting the PDK1 and SGLT2 expressions in the NTS. These results indicate that SGK1 regulates the cardiometabolic syndrome in the NTS of CKD rats.Support or Funding Information107‐2320‐B‐075B‐002‐MY2、107‐2320‐B‐075B‐001