&lt;b&gt;PPARα induced NOS1 phosphorylation via PI3K/Akt in guinea pig antral mucous cells: NO-enhancement in Ca&lt;/b&gt;&lt;sup&gt;&lt;b&gt;2+&lt;/b&gt;&lt;/sup&gt;&lt;b&gt;-regulated &lt;/b&gt;&lt;b&gt;exocytosis &lt;/b&gt;

Tanaka, Saori; Hosogi, Shigekuni; Sawabe, Yukinori; Shimamoto, Chikao; Matsumura, Hitoshi; Inui, Toshio; Marunaka, Yoshinori; Nakahari, Takashi

doi:10.2220/biomedres.37.167

Cited by 9 publications

(11 citation statements)

References 31 publications

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“…Moreover, in cultured human renal cortex tissue, hanging drop medium with a high concentration of glucose increased NOS1 expression and stimulated the NOS1 phosphorylation at Ser1417. Regarding potential mechanisms, on the basis of the related literature, we speculate that glucose upregulates NOS1 expression and phosphorylates NOS1 via the PI3K/Akt [65][66][67][68][69] and/or cAMP/PKA [70][71][72][73][74] pathways.…”

Section: Glucose-induced Hyperfiltration Is Mediated By Macula Densa mentioning

confidence: 90%

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Zhang¹,

Jin²,

Jiang³

et al. 2019

JASN

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Background Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. Methods We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice. Results Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. Conclusions We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

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Section: Glucose-induced Hyperfiltration Is Mediated By Macula Densa mentioning

confidence: 90%

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Zhang¹,

Jin²,

Jiang³

et al. 2019

JASN

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“…Bodily and cellular functions are controlled by various factors including ions such as Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ , and Cl − [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. On the one hand, pH (−log[H + ]) is recognized as one of classical items considered to be already fully understood in roles and mechanisms of homeostasis.…”

Section: Variety Of the Interstitial Fluid Phmentioning

confidence: 99%

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

Marunaka

2018

IJMS

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Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO−) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO−) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus.

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“…The solution was aerated with a gas mixture (95% O 2 and 5% CO 2 ) at 37 • C. Acetylcholine chloride (ACh) was purchased from Daiichi Sankyo company (Tokyo, Japan). Collagenase (for cell dispersion, 260-280 units/mg), bovine serum albumin (BSA), dimethyl sulfoxide (DMSO), arachidonyl trifluoromethyl ketone (AACOCF3), ionomycin (IM), indomethacin (IDM), acetylsalicylic acid (aspirin; ASA), chloroform and n-heptane were purchased from Wako Pure Chemical Industries (Osaka, Japan); cPLA2-inhα (a PLA2 inhibitor) (Fujiwara et al, 1999(Fujiwara et al, , 2006Nakahari et al, 2002;Ohnishi et al, 2001;Saad et al, 2006;Sawabe et al, 2010;Shimamoto et al, 2005Shimamoto et al, , 2006Shimamoto et al, , 2007Tanaka et al, 2013Tanaka et al, , 2014Tanaka et al, , 2016.…”

Section: Solution and Chemicalsmentioning

confidence: 99%

“…There are many reports showing that NO production is activated by an increase in [Ca 2+ ] i (Förstermann & Sessa, 2012;Pereira et al, 2011;Zuccolo et al, 2017). Moreover, arachidonic acid (AA) has also been shown to stimulate NO synthesis in vascular endothelial cells (Fiorio Pla & Munaron, 2001;Fiorio Pla et al, 2010;Kohler et al, 2006;Moneer et al, 2003;Mottola et al, 2005), parotid acinal cells (Watson et al, 2004) and antral mucous cells (Sawabe et al, 2010;Tanaka et al, 2014Tanaka et al, , 2016.…”

mentioning

confidence: 99%

“…In antral mucous cells, prostaglandin E 2 (PGE 2 ) enhances Ca 2+ -regulated exocytosis via cAMP accumulation (Nakahari et al, 2002;Shimamoto et al, 2005). Moreover, in antral mucous cells, AA alone phosphorylates NOS1 by stimulating peroxisome proliferation-activated receptor α (PPARα) and stimulates NO synthesis leading to cGMP accumulation, which enhances Ca 2+ -regulated exocytosis (Saad et al, 2006;Sawabe et al, 2010;Tanaka et al, 2014Tanaka et al, , 2016. Thus, AA appears to be a key substance for NO production in antral mucous cells during ACh stimulation.…”

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confidence: 99%

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Nitric oxide synthesis stimulated by arachidonic acid accumulation via PPARα in acetylcholine‐stimulated gastric mucous cells

Tanaka

Ito

Shimamoto

et al. 2021

Experimental Physiology

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In the present study, we demonstrate that NO production is stimulated by an accumulation of arachidonic acid (AA) mediated via peroxisome proliferation-activated receptor α (PPARα) and that the NO produced enhances Ca 2+ -regulated exocytosis in ACh-stimulated antral mucous cells. The amount of AA released from the antral mucosa, measured by fluorescence high-performance liquid chromatography (F-HPLC), was increased by addition of ionomycin (10 μM) or ACh, suggesting that AA accumulation is stimulated by an increase in [Ca 2+ ] i . The AA production was inhibited by an inhibitor of cytosolic phospholipase A2 (cPLA2-inhα). GW6471 (a PPARα inhibitor) and cPLA2-inhα inhibited NO synthesis stimulated by ACh. Moreover, indomethacin, an inhibitor of cyclooxygenase, stimulated AA accumulation and NO production. However, acetylsalicylic acid did not stimulate AA production and NO synthesis. An analogue of AA (AACOCF3) alone stimulated NO synthesis, which was inhibited by GW6471. In antral mucous cells, indomethacin enhanced Ca 2+ -regulated exocytosis by increasing NO via PPARα, and the enhancement was abolished by GW6471 and cPLA2-inhα. Thus, AA produced via PLA2 activation is the key step for NO synthesis in ACh-stimulated antral mucous cells and plays important roles in maintaining antral mucous secretion, especially in Ca 2+ -regulated exocytosis. K E Y W O R D Sindomethacin, intracellular Ca 2+ concentration, mucin exocytosis, nitric oxide, peroxisome proliferation-activated receptor α, phospholipase A2 INTRODUCTIONNitric oxide (NO) is a ubiquitous molecule for inter-or intracellular signalling in many tissues and cell types (Hardingham et al., 2013;

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<b>PPARα induced NOS1 phosphorylation via PI3K/Akt in guinea pig antral mucous cells: NO-enhancement in Ca</b><sup><b>2+</b></sup><b>-regulated </b><b>exocytosis </b>

Cited by 9 publications

References 31 publications

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

Nitric oxide synthesis stimulated by arachidonic acid accumulation via PPARα in acetylcholine‐stimulated gastric mucous cells

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