Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression

Khan, Shenaz; Gaivin, Robert J.; Abramovich, Caroline M.; Boylan, Michael O.; Calles, Jorge; Schelling, Jeffrey R.

doi:10.1172/jci.insight.136845

Cited by 44 publications

(36 citation statements)

References 64 publications

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“…The toxic effect of FA on the renal tubular epithelial cells is associated with hypoxia and mitochondrial dysfunction ( 33 , 84 ). A recent study has shown that FATP2, a member of the fatty acid transporter family, regulates DKD pathogenesis through a combined lipotoxicity and glucotoxicity (glucolipotoxicity) mechanism ( 85 ). Nevertheless, PBI-4050, which is a fatty acid receptor modulator, attenuates the development of DKD in type 2 diabetes ( 86 ).…”

Section: Fatty Acidsmentioning

confidence: 99%

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Chang

Yan

et al. 2021

Front. Med.

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Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.

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Section: Fatty Acidsmentioning

confidence: 99%

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Chang

Yan

et al. 2021

Front. Med.

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“…Both models were bred to a congenic C57BLKS/J genetic background, which renders a more severe DKD phenotype. In particular, both strains develop progressive decreases in GFR 19 , which is a risk for VT/VF and SCD in humans 3 – 9 . Baseline characteristics for wild-type mice and the two DKD strains are shown in Table S1 (supplement).…”

Section: Resultsmentioning

confidence: 99%

“…However, Lepr db/db combined with eNOS −/− ( Lepr db/db eNOS −/− ) permits a faithful phenocopy of type 2 diabetes and DKD, including decreased GFR, interstitial fibrosis and tubular atrophy 14 , 15 . Lepr db/db eNOS −/− mice also die suddenly and prematurely 14 , 16 – 19 , suggesting that the final event may be an arrhythmia and SCD.…”

Section: Introductionmentioning

confidence: 99%

“…Streptozotocin (STZ) has been used to induce type 1 diabetes and DKD in rodents, but the high doses required to completely obliterate pancreatic β-cells, inflict tubular toxicity, which may confound the renal phenotype 32 . However, low dose STZ combined with a HFD second hit mimics obesity, type 2 diabetes and DKD, including decreased GFR 19 , 32 – 34 .…”

Section: Introductionmentioning

confidence: 99%

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Ventricular arrhythmias in mouse models of diabetic kidney disease

Laurita

Khan

McMahon

et al. 2021

Sci Rep

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Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates. Compared to wild-type mice, both Leprdb/db eNOS−/− (2KO) and high fat diet plus low dose streptozotocin (HFD + STZ) mouse models of DKD experienced sudden death and greater arrhythmia inducibility, which was more common with isoproterenol than programmed electrical stimulation. 2KO mice demonstrated slowed conduction velocity, prolonged action potential duration (APD), and myocardial fibrosis; both 2KO and HFD + STZ mice exhibited arrhythmias and calcium dysregulation with isoproterenol challenge. Finally, circulating concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) were elevated in 2KO mice. Incubation of human cardiac myocytes with ADMA prolonged APD, as also observed in 2KO mice hearts ex vivo. The present study elucidates an arrhythmia-associated mechanism of sudden death associated with DKD, which may lead to more effective treatments in the vulnerable DKD patient population.

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“…FATP2 plays a crucial role in a variety of diseases, including non-alcoholic fatty liver disease (NAFLD) [214], type 2 diabetes mellitus (T2DM) [215], lithogenic diet-induced cholelithiasis [216], cancer [217,218] and chronic kidney disease (CKD) [215,219]. Additionally, both FATP2 and FATP5 have been shown to contribute to the etiology of hepatic steatosis [211,212,220], making them potential targets for novel treatment options.…”

Section: Fatp2 and Fatp5mentioning

confidence: 99%

Investigating the mechanism of action of TMEM16 scramblases and FATP fatty acid transporters

Mosina¹

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Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression

Cited by 44 publications

References 64 publications

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Ventricular arrhythmias in mouse models of diabetic kidney disease

Investigating the mechanism of action of TMEM16 scramblases and FATP fatty acid transporters

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