Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules

Li, Jinpeng; Liu, Haijie; Takagi, Susumu; Nitta, Kyoko; Kitada, Munehiro; Srivastava, Swayam Prakash; Takagaki, Yuta; Kanasaki, Keizo; Koya, Daisuke

doi:10.1172/jci.insight.129034

Cited by 137 publications

(121 citation statements)

References 49 publications

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“…The subcellular distribution of SIRT3 is disturbed which results in less SIRT3 in the mitochondria and cytosol [161]. Moreover, a suppressed level of SIRT3 in the cytosol leads to defective glucose metabolism, by inducing PKM2 dimer formation, HIFα accumulation and STAT3 phosphorylation [160][161][162]. Such mechanisms are similar to the Warburg effect observed in tumor metabolism.…”

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 88%

“…Figure 2 depicts a hypothetical scheme showing the critical role of SGLT2 in aberrant glucose metabolism and associated EMT in diabetic kidneys. In this figure we describe diabetic tubular epithelial cells (TECs) that express higher levels of SGLT-2 on the luminal side and GLUT2 on the basolateral side [160,161]. In diabetic epithelial cells, glucose is absorbed from the urine into the cell through SGLT-2 and this absorbed glucose is transported efficiently out of tubular cells by GLUT2 [160,161].…”

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

“…In this figure we describe diabetic tubular epithelial cells (TECs) that express higher levels of SGLT-2 on the luminal side and GLUT2 on the basolateral side [160,161]. In diabetic epithelial cells, glucose is absorbed from the urine into the cell through SGLT-2 and this absorbed glucose is transported efficiently out of tubular cells by GLUT2 [160,161]. In diabetes mellitus, higher expression of SGLT-2 increases the absorbing capacity of glucose from urine into TECs, as compared to the ability of GLUT2 to transport the glucose out of TECs [160].…”

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

“…In diabetic epithelial cells, glucose is absorbed from the urine into the cell through SGLT-2 and this absorbed glucose is transported efficiently out of tubular cells by GLUT2 [160,161]. In diabetes mellitus, higher expression of SGLT-2 increases the absorbing capacity of glucose from urine into TECs, as compared to the ability of GLUT2 to transport the glucose out of TECs [160]. In this diabetic condition, glucose accumulates in the cells, which results in the suppression of SIRT3 [161].…”

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

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Cancer Biology and Prevention in Diabetes

Srivastava

Goodwin

2020

Cells

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The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

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Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 88%

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

Section: Sodium-glucose Cotransporter 2 Inhibitors In Cancermentioning

confidence: 99%

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Cancer Biology and Prevention in Diabetes

Srivastava

Goodwin

2020

Cells

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“…Glycolysis inhibitors or PKM2 activators disrupt such metabolic reprogramming resulting in significant suppression of fibrosis, indicating that they can be utilized as a new therapeutic approach to combate diabetic kidney complications (Qi et al, 2017; Srivastava et al, 2018). A recent preclinical study suggests that sodium glucose transporter 2 inhibition abolished the defective glucose metabolism and associated epithelial‐to‐mesenchymal transitions in the diabetic kidneys, resulting in remarkable improvements in the kidney's structure, functions and fibrosis (Li et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

Srivastava

Goodwin

Kanasaki

et al. 2020

British J Pharmacology

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Background and Purpose ACE inhibitors (ACEIs) and AT1 receptor antagonists (ARBs) are first‐line drugs that are believed to reduce the progression of end‐stage renal disease in diabetic patients. Differences in the effects of ACEIs and ARBs are not well studied and the mechanisms responsible are not well understood. Experimental Approach Male diabetic CD‐1 mice were treated with ACEI, ARB, N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP), ACEI + AcSDKP, ARB + AcSDKP, glycolysis inhibitors or non‐treatment. Moreover, prolyl oligopeptidase inhibitor (POPi)‐injected male diabetic C57Bl6 mice were treated with ACEI, AcSDKP and ARB or non‐treatment. Western blot and immunofluorescent staining were used to examine key enzymes and regulators of central metabolism. Key Results The antifibrotic action of ACEI imidapril is due to an AcSDKP‐mediated antifibrotic mechanism, which reprograms the central metabolism including restoring SIRT3 protein and mitochondrial fatty acid oxidation and suppression of abnormal glucose metabolism in the diabetic kidney. Moreover, the POPi S17092 significantly blocked the AcSDKP synthesis, accelerated kidney fibrosis and disrupted the central metabolism. ACEI partly restored the kidney fibrosis and elevated the AcSDKP level, whereas the ARB (TA‐606) did not show such effects in the POPi‐injected mice. ACE inhibition and AcSDKP suppressed defective metabolism‐linked mesenchymal transformations and reduced collagen‐I and fibronectin accumulation in the diabetic kidneys. Conclusion and Implications The study envisages that AcSDKP is the endogenous antifibrotic mediator that controls the metabolic switch between glucose and fatty acid metabolism and that suppression of AcSDKP leads to disruption of kidney cell metabolism and activates mesenchymal transformations leading to severe fibrosis in the diabetic kidney.

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Renal Tubular Handling of Glucose and Fructose in Health and Disease

Vallon

Nakagawa

2021

Comprehensive Physiology

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Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules

Cited by 137 publications

References 49 publications

Cancer Biology and Prevention in Diabetes

Cancer Biology and Prevention in Diabetes

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

Renal Tubular Handling of Glucose and Fructose in Health and Disease

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