Npt2a as a target for treating hyperphosphatemia

Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma Pi levels. In addition, a paradoxical increase in expression of intestinal Pi transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/Pi cotransporter 2a (Npt2a), responsible for ∼70% of Pi reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary Pi excretion consequently lowering plasma Pi and PTH levels. Additionally, increases in urinary excretions of Na+, Cl− and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on Pi homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.

Endocan: A Key Player of Cardiovascular Disease

Endothelial dysfunction is considered to be an early change in atherosclerosis. Endocan, also known as endothelial cell specific molecule-1, is a soluble proteoglycan mainly secreted by endothelial cells. Inflammatory factors such as IL-1β and TNF-α can up regulate the expression of endocan and then affect the expression of cell adhesion molecules, such as ICAM-1 and VCAM-1, which play an important role in promoting leukocyte migration and inflammatory response. Elevated plasma levels of endocan may reflect endothelial activation and dysfunction, and is considered to be a potential immuno-inflammatory marker that may be related to cardiovascular disease. In the case of hypertension, diabetes, angina pectoris and acute myocardial infarction, the increase or decrease of serum endocan levels is of great significance. Here, we reviewed the current research on endocan, and emphasis its possible clinical value as a prognostic marker of cardiovascular disease. Endocan may be a useful biomarker for the prognosis of cardiovascular disease, but more research is needed on its mechanism of action.

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex . Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

Elevated Plasma Level of the Glycolysis Byproduct Methylglyoxal on Admission Is an Independent Biomarker of Mortality in ICU COVID-19 Patients

Biomarkers to identify ICU COVID-19 patients at high risk for mortality are urgently needed for therapeutic care and management. In this study we found that plasma levels of the glycolysis byproduct methylglyoxal (MG) were 4.4-fold and 1.7-fold higher (P<0.0001) upon ICU admission in patients that later died (n=34) compared to uninfected controls (n=30) and those survived (n=31), respectively. The increase in MG was inversely correlated with glutathione (r2=-0.63) and the MG-glutathione degrading glyoxalase-1 (r2=-0.50), and positively correlated with the inflammation markers, SSAO (r2 =0.52), TNF-a (r2 =0.41), IL-1b (r2 =0.25), CRP (r2 =0.26) and age (r2 =0.20). Logistic regression analysis provides evidence of a significant relationship between the elevated MG upon admission into ICU and death (P<0.0001), with 42% of the death variability explained. From these data we conclude that elevated plasma MG on admission is a novel independent biomarker that predicts ICU COVID-19 patients at high risk of mortality.

Human IAPP is a driver of painful diabetic peripheral neuropathy

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM), of which the pathogenesis is not fully understood. We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth. Transgenic hIAPP Ob/Ob mice, an established animal model for T2DM, as well as hIAPP mice, which have elevated plasma hIAPP levels but no hyperglycaemia. Both transgenic mice developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fibers (IENF), suggesting hIAPP is a mediator of diabetic neuropathy. Intraplantar and intravenous hIAPP injection in WT mice induced long-lasting mechanical hypersensitivity and reduced IENF, whereas non-aggregating murine IAPP or mutated hIAPP (Pramlintide) did not have these effects, and were not toxic for cultured sensory neurons. In T2DM patients, significantly more hIAPP oligomers were found in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP is toxic to sensory neurons, and mediates peripheral neuropathy in mice. The presence of hIAPP aggregates in skin of humans with T2DM supports the notion that human IAPP is a potential driver of T2DM neuropathy in man.