A novel therapeutic effect of statins on nephrogenic diabetes insipidus

Bonfrate, Leonilde; Procino, Giuseppe; Wang, David Q.–H.; Svelto, María; Portincasa, Piero

doi:10.1111/jcmm.12422

Cited by 30 publications

(27 citation statements)

References 259 publications

(336 reference statements)

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“…36 Of all patients taking lithium, up to 55% of the patients report various degrees of NDI, requiring them to make major lifestyle modifications, including continuous access to water and frequent voiding to avoid hydronephrosis and bladder dilation/dysfunction. 10 This complication can significantly affect quality of life and add substantial burdens to these psychologically compromised populations. Dysregulation of AQPs in the collecting duct is a crucial mechanism for the development of lithium-induced NDI, but the exact mechanism of how lithium causes NDI is not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…50 Some of these potential therapeutic strategies included activating the cAMP pathway using calcitonin to increase cAMP levels via GaS activation, 11 stimulating the nitric oxide/cGMP pathway with the phosphodiesterase inhibitor sildenafil, 13,51 affecting the PGE2 pathway using the COX-2 inhibitor celecoxib, 52,53 or modulating the actin cytoskeleton network with statins to decrease AQP2 endocytosis. 9,10 These approaches seem promising, but perhaps because lithium exerts such a complex effect on AQP2 trafficking and collecting duct morphology, none of them have yet been shown to provide sustainable benefits in patients. .…”

Section: Discussionmentioning

confidence: 99%

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EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

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Nephrogenic diabetes insipidus (NDI) is caused by impairment of vasopressin (VP) receptor type 2 signaling. Because potential therapies for NDI that target the canonical VP/cAMP/protein kinase A pathway have so far proven ineffective, alternative strategies for modulating aquaporin 2 (AQP2) trafficking have been sought. Successful identification of compounds by our high-throughput chemical screening assay prompted us to determine whether EGF receptor (EGFR) inhibitors stimulate AQP2 trafficking and reduce urine output. Erlotinib, a selective EGFR inhibitor, enhanced AQP2 apical membrane expression in collecting duct principal cells and reduced urine volume by 45% after 5 days of treatment in mice with lithiuminduced NDI. Similar to VP, erlotinib increased exocytosis and decreased endocytosis in LLC-PK1 cells, resulting in a significant increase in AQP2 membrane accumulation. Erlotinib increased phosphorylation of AQP2 at Ser-256 and Ser-269 and decreased phosphorylation at Ser-261 in a dose-dependent manner. However, unlike VP, the effect of erlotinib was independent of cAMP, cGMP, and protein kinase A. Conversely, EGF reduced VP-induced AQP2 Ser-256 phosphorylation, suggesting crosstalk between VP and EGF in AQP2 trafficking and a role of EGF in water homeostasis. These results reveal a novel pathway that contributes to the regulation of AQP2-mediated water reabsorption and suggest new potential therapeutic strategies for NDI treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

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“…The diagnosis was in line with the diagnostic criteria and classification of diabetes of World Health Organization (WHO) in 1999 [13]. All the patients were subjected to a detailed medical examination and fundus ophthalmoscope examination by using a Canon non-mydriasis retinal camera (Canon, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Plasma miR-21 expression: an indicator for the severity of Type 2 diabetes with diabetic retinopathy

et al. 2017

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To investigate the roles of plasma miR-21 in the pathogenic process of Type 2 diabetes (T2D) with diabetic retinopathy (DR). T2D patients included patients without DR (NDR) group, patients with non-proliferative/background DR (BDR) group and patients with proliferative DR (PDR) group. Healthy individuals served as control group. Fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), triacylglycerol (TG), total cholesterol (TC), urine creatinine (Cr), fasting blood glucose (FBG), blood urea nitrogen (BUN), low-density lipoprotein cholesterol (LDL-C), fasting insulin (FINS) and plasma miR-21 expression were measured. Quantitative real-time PCR (qRT-PCR) was applied to detect miR-21 expression. Pearson analysis was used to conduct correlation analysis and receiver operating characteristic (ROC) curve was used to analyse the diagnostic value of miR-21 in T2D with DR. Compared with the control group, FBG and HbA1c increased in the NDR group; compared with the control and NDR groups, disease course, HbA1c, FPG levels and homoeostasis model assessment of insulin resistance (HOMA-IR) were increased in the BDR and PDR groups; and compared with the BDR group, disease course, HbA1c and FPG levels were higher in the PDR group. miR-21 expression was higher in the BDR group than the control group, and higher in the PDR group than the BDR group. miR-21 expression was positively related with disease course, HbA1C, FPG and HOMA-IR, and had diagnostic value for T2D with DR and PDR. The plasma miR-21 expression was increased in the development of T2D with DR and can be used as an indicator for the severity of T2D with DR.

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“…Hyperlipidaemia is an important atherogenic factor by promoting the formation and accumulation of lipid plaques in the arteries . Currently, statins are the leading lipid‐lowering drugs that inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, the rate‐limiting enzyme for de novo synthesis of cholesterol . However, increasing numbers of studies have reported side effects of statins .…”

Section: Introductionmentioning

confidence: 99%

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

Pang

et al. 2020

J Cellular Molecular Medi

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Recent studies have demonstrated that commercially available lipid‐lowering drugs cause various side effects; therefore, searching for anti‐hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine‐derived compound, 5‐hydroxy‐3‐methoxy‐5‐methyl‐4‐butylfuran‐2(5H)‐one, has an anti‐hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox‐LDL‐induced lipid accumulation (~50%), and its triglyceride (TG)‐lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator‐activated receptors (PPARα) and ATP‐binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid‐induced lipid accumulation, enhanced the protein levels of low‐density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element‐binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone‐induced lipid‐lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC‐ and TG‐lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.

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A novel therapeutic effect of statins on nephrogenic diabetes insipidus

Cited by 30 publications

References 259 publications

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Plasma miR-21 expression: an indicator for the severity of Type 2 diabetes with diabetic retinopathy

The marine‐derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα

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