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• W4378649861 abstract "Introduction: Glucagon is raised during hypoglycemia in order to bring blood glucose back to normal levels. However, glucagon is paradoxically also raised under pathophysiological conditions where plasma glucose is high such as in diabetes mellitus (DM). DM is associated with hypertension, which contributes to diabetic kidney disease and other co-morbidities. The NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT) contributes to blood pressure control and the DCT also expresses the glucagon receptor. Therefore, we hypothesized that glucagon directly stimulates NCC via the glucagon receptor, and this may be a novel mechanism to modulate blood pressure. Methods: In vivo effects on NCC were studied in mice injected with glucagon. Ex vivo kidney tubules isolated from mouse and human kidney (obtained from tumor nephrectomized patients) were cultured and exposed to varying doses of glucagon alone, or in the presence of various inhibitors. The phosphorylation status of NCC was used as a surrogate marker for activity (increased phosphorylation = increased activity). Results: In kidneys isolated from mice 30 min after being injected with glucagon, NCC phosphorylation was increased. In ex vivo mouse kidney tubules, glucagon (1 nM to 1000 nM) exposure for 30 min increased NCC phosphorylation in a dose-dependent manner. 10 nM glucagon increased NCC phosphorylation after 5 min, an effect lasting up to 4 h. The glucagon receptor inhibitor 168,049 completely blocked the effect of 10 nM glucagon on NCC phosphorylation. The With No Lysine kinase (WNK) inhibitor StockS2, the inward-rectifier potassium channel 4.1/5.1 (Kir 4.1/5.1) inhibitor VU0134992, and the non-specific protein kinase A (PKA) inhibitor, H89, greatly reduced the effect of 10 nM glucagon on NCC phosphorylation. NCC phosphorylation was also increased in ex vivo human kidney slices exposed to 100 nM glucagon. Conclusion: We show for the first time that glucagon increases NCC phosphorylation in the mouse kidney both in vivo and ex vivo. The effect occurs via the glucagon receptor and involves WNK kinases, Kir4.1/5.1 and PKA. Glucagon effects can be observed ex vivo in human kidney slices, supporting that the findings may be relevant in humans. Whether glucagon-induced NCC phosphorylation contributes to the etiology of pathophysiological conditions manifested with raised plasma glucagon levels, such as DM, remains to be investigated. Novo Nordisk Foundation (NNF21OC0067647) and the Leducq Foundation (17CVD05). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process." @default.
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• W4378649861 date "2023-05-01" @default.
• W4378649861 modified "2023-09-25" @default.
• W4378649861 title "Glucagon activates NCC in a glucagon receptor-dependent manner" @default.
• W4378649861 doi "https://doi.org/10.1152/physiol.2023.38.s1.5732351" @default.
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