Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome

Nakamura, Motonobu; Yamazaki, Osamu; Shirai, Ayumi; Horita, Shoko; Satoh, Nobuhiko; Suzuki, Masashi; Hamasaki, Yoshifumi; Noiri, Eisei; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George

doi:10.1038/ki.2014.351

Cited by 51 publications

(79 citation statements)

References 48 publications

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“…These phenotypes are not seen in PT-specific IRS1 or IRS2 single-knockout mice, suggesting that each of the IRSs can compensate for the lack of the other in the PTs. This redundancy is not seen in insulin-mediated sodium reabsorption in the PTs, in which IRS2 plays a pivotal role (35,36), or in the regulation of glucose and lipid metabolism in the liver, in which IRS1 and IRS2 show functional differences (16), although FoxO1 is shared as the key downstream molecule of insulin signaling.…”

Section: Discussionmentioning

confidence: 96%

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

et al. 2017

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Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs.

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Section: Discussionmentioning

confidence: 96%

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

et al. 2017

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“…Adipokines released from adipose tissue in obesity are related to increased sympathetic nerve activity, 37 and insulin resistance (reflected by homeostasis model assessment-insulin resistance index) may also promote hypertension. 38 These factors working in concert might increase MAP in Obese-HT compared to Lean-HT. Due to increased pressure load, cardiac oxygen demand (rate-pressure-product) rises.…”

Section: Discussionmentioning

confidence: 98%

Cardiac Metabolic Alterations in Hypertensive Obese Pigs

Zhang

Eirin

et al. 2015

Hypertension

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Obesity and hypertension are major risk factors for cardiovascular diseases, and their growing coexistence accounts for an increase in adverse cardiac events, but the mechanisms are yet to be determined. We hypothesized that obesity exacerbates mitochondrial dysregulation imposed by hypertension and augments left ventricular dysfunction. Obesity-prone Ossabaw pigs were randomized to lean (standard diet) and obese (high-fat diet), without (Lean-sham, Obese-sham) or with renovascular hypertension (Lean-Hypertension, Obese-Hypertension), induced after 12 weeks of diet (n=7 each). Cardiac function, myocardial perfusion and oxygenation, and microvascular remodeling were assessed 4 weeks later. Mitochondrial biogenesis signals and structural proteins, respiratory chain complex activities, and mitochondrial self-degradation were examined, as was fibrosis. Obesity alone exerted no apparent effect on mitochondrial dynamics, but aggravated in hypertensive hearts the reduction of mitochondrial proteins, deoxyribonucleic acid content, and respiratory chain complex IV subunits activity, and amplified mitochondrial self-degradation. Synergistic interaction of obesity with hypertension also exacerbated myocardial fibrosis and left ventricular diastolic dysfunction. Mitochondrial content, respiratory chain complex IV subunits activity, and mitophagy were correlated with myocardial fibrosis. These findings suggest that obesity aggravates in renovascular hypertension cardiac mitochondrial aberrations. Mitochondrial function may regulate the progression of cardiac injury and functional deterioration in hypertension concomitant with obesity.

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“…We also observed that IR markers were more pronounced in SAH than in normal blood pressure in all groups, that is, women with c-PCOS, ov-PCOS, and controls. Indeed, IR-related compensatory hyperinsulinemia may influence blood pressure through an autonomic nervous system imbalance (30,31), increased renal sodium reabsorption, and decreased nitric oxide production (32)(33)(34) in distinct populations. Regarding PCOS phenotypes, we have previously shown that patients with c-PCOS present subclinical autonomic dysfunction in comparison with controls, and that women with ov-PCOS present intermediate heart rate variability indexes in relation to c-PCOS and control groups (10).…”

Section: Figurementioning

confidence: 99%

ACC/AHA 2017 definition of high blood pressure: implications for women with polycystic ovary syndrome

Marchesan

Spritzer

2019

Fertility and Sterility

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Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome

Cited by 51 publications

References 48 publications

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

Cardiac Metabolic Alterations in Hypertensive Obese Pigs

ACC/AHA 2017 definition of high blood pressure: implications for women with polycystic ovary syndrome

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