Elevated phosphate mediates extensive cellular toxicity: from abnormal proliferation to excessive cell death

He, Ping; Mann‐Collura, Olivia; J, Fling; Edara, Naga; Ms, Razzaque

doi:10.1101/2020.01.02.892638

Cited by 3 publications

(2 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another class of SGLT2i, Dapagliflozin, has also been vindicated and shows propensity to leverage the negative vasoconstrictive effects of phosphate and hyperglycemia mediated ROS as demonstrated by Li et al [ 103 ]. The ability for SGLT2i to reduce blood pressure was examined via application of dapagliflozin on the aortic rings of male New Zealand white rabbits.…”

Section: Hyperphosphatemia Sglt2 and Cardiorenal Implicationsmentioning

confidence: 99%

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Nashawi¹,

Ahmed²,

Amin³

et al. 2021

WJC

View full text Add to dashboard Cite

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

show abstract

Section: Hyperphosphatemia Sglt2 and Cardiorenal Implicationsmentioning

confidence: 99%

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Nashawi¹,

Ahmed²,

Amin³

et al. 2021

WJC

View full text Add to dashboard Cite

show abstract

“…lung, Supplemental Figure 1b). Thus, under conditions of high SLC34A2 expression, loss of XPR1 or KIDINS220 leads to the intracellular accumulation of inorganic phosphate, which has previously been shown to be toxic to cells 49,50 . The experiments described here thus provide a rationale for the development of therapeutic strategies aimed at inhibiting XPR19 or KIDINS220 51 Figure 4: Protein efflux is achieved by the XPR1:KIDINS220 protein complex and perturbation of this complex causes accumulation of acidic 'vacuole' structures a.…”

mentioning

confidence: 99%

Phosphate dysregulation via the XPR1:KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer

Bondeson

Paolella

Asfaw

et al. 2020

Preprint

View full text Add to dashboard Cite

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

show abstract

Management of Fluids and Electrolytes in Onco-Critical Patient

et al. 2022

View full text Add to dashboard Cite

Elevated phosphate mediates extensive cellular toxicity: from abnormal proliferation to excessive cell death

Cited by 3 publications

References 51 publications

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Phosphate dysregulation via the XPR1:KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer

Management of Fluids and Electrolytes in Onco-Critical Patient

Contact Info

Product

Resources

About