SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition

Tomita, Issei; Kume, Shinji; Sugahara, Sho; Osawa, Norihisa; Yamahara, Kosuke; Yasuda‐Yamahara, Mako; Takeda, Naoko; Chin‐Kanasaki, Masami; Kaneko, Takuma; Mayoux, Eric; Michael, Mark; Yanagita, Motoko; Ogita, Hisakazu; Araki, Shin‐ichi; Maegawa, Hiroshi

doi:10.1016/j.cmet.2020.06.020

Cited by 211 publications

(187 citation statements)

References 56 publications

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“…Given its glycosuric effects, SGLT2i remarkably alters cellular metabolism in proximal tubules and, possibly, podocytes [6], toward a nutritional deprivation state, and thereby activates the AMPK pathway. Moreover, recent data support that SGLT2i augment ketolysis and inhibit mTORC1-an effect that ostensibly increases autophagy [7].…”

mentioning

confidence: 89%

Totally tubular, dude: rethinking DKD pathogenesis in the wake of SGLT2i data

Leventhal

Cravedi

2020

J Nephrol

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mentioning

confidence: 89%

Totally tubular, dude: rethinking DKD pathogenesis in the wake of SGLT2i data

Leventhal

Cravedi

2020

J Nephrol

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“…A recent preclinical study revealed that empagliflozin increased ketone bodies, which subsequently inhibited the mTORC1 pathway in the proximal tubular cells. 72 Another SGLT2 inhibitor, ipragliflozin, ameliorated abnormal accumulation of tricarboxylic acid cycle metabolites within the kidneys of type 2 diabetic mice. 73 Other mechanisms are also being proposed, including reduced oxidative stress, improvement of cortical hypoxia, and vascular remodelling.…”

Section: Similar Cardiovascular and Kidney Protection Was Reported Inmentioning

confidence: 99%

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

et al. 2021

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Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria.Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose-lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.

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“…Interestingly, ketones were found to inhibit mTOR signaling in diabetic kidney disease as a mechanism for SGLT2 inhibition-mediated renoprotection. 53 Signaling and utilization of ketone bodies are further facilitated by up-regulation of circulating ketone body concentrations in response to heart failure. 54 This can be attributed to adrenergic signaling providing adipose tissue lipolysis and hepatic ketone body production.…”

Section: Pascal Alexander Mann and Michael Lehrke MDmentioning

confidence: 99%