Fatty acids and inflammatory stimuli induce expression of long-chain acyl-CoA synthetase 1 to promote lipid remodeling in diabetic kidney disease.

Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD. However, the roles of specific enzymes involved in lipid remodeling in DKD have not been elucidated. In the present study, we used this diabetic mouse model and a proximal tubule epithelial cell line (HK2) to investigate the potential relationship between long-chain acyl-CoA synthetase 1 (ACSL1) and lipid metabolism in response to fatty acid exposure and inflammatory signals. We found ACSL1 expression was significantly increased in the kidney cortex of db/db mice, and exposure to palmitate or tumor necrosis factor-α significantly increased Acsl1 mRNA expression in HK-2 cells. In addition, palmitate treatment significantly increased the levels of long-chain acylcarnitines and fatty acyl CoAs in HK2 cells, and these increases were abolished in HK2 cell lines with specific deletion of Acsl1(Acsl1KO cells), suggesting a key role for ACSL1 in fatty acid ß-oxidation. In contrast, tumor necrosis factor-α treatment significantly increased the levels of short-chain acylcarnitines and long-chain fatty acyl CoAs in HK2 cells but not in Acsl1KO cells, consistent with fatty acid channeling to complex lipids. Taken together, our data demonstrate a key role for ACSL1 in regulating lipid metabolism, fatty acid partitioning, and inflammation.

Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis.

BACKGROUND: Cisplatin is effective against various types of cancers. However, its clinical application is limited owing to its adverse effects, especially acute kidney injury (AKI). Dihydromyricetin (DHM), a flavonoid derived from Ampelopsis grossedentata, has varied pharmacological activities. This research aimed to determine the molecular mechanism for cisplatin-induced AKI. METHODS: A murine model of cisplatin-induced AKI (22 mg/kg, I.P.) and a HK-2 cell model of cisplatin-induced damage (30 µM) were established to evaluate the protective function of DHM. Renal dysfunction markers, renal morphology and potential signaling pathways were investigated. RESULTS: DHM decreased the levels of renal function biomarkers (blood urea nitrogen and serum creatinine), mitigated renal morphological damage, and downregulated the protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It upregulated the expression levels of antioxidant enzymes (superoxide dismutase and catalase expression), nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream proteins, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, thus eventually reducing cisplatin-induced reactive oxygen species (ROS) production. Moreover, DHM partially inhibited the phosphorylation of the active fragments of caspase-8 and -3 and mitogen-activated protein kinase and restored glutathione peroxidase 4 expression, which attenuated renal apoptosis and ferroptosis in cisplatin-treated animals. DHM also mitigated the activation of NLRP3 inflammasome and nuclear factor (NF)-κB, attenuating the inflammatory response. In addition, it reduced cisplatin-induced HK-2 cell apoptosis and ROS production, both of which were blocked by the Nrf2 inhibitor ML385. CONCLUSIONS: DHM suppressed cisplatin-induced oxidative stress, inflammation and ferroptosis probably through regulating of Nrf2/HO-1, MAPK and NF-κB signaling pathways.

Intratubular, Intracellular, and Mitochondrial Angiotensin II/AT1 (AT1a) Receptor/NHE3 Signaling Plays a Critical Role in Angiotensin II-Induced Hypertension and Kidney Injury.

Hypertension is well recognized to be the most important risk factor for cardiovascular diseases, stroke, and end-stage kidney failure. A quarter of the world's adult populations and 46% of the US adults develop hypertension and currently require antihypertensive treatments. Only 50% of hypertensive patients are responsive to current antihypertensive drugs, whereas remaining patients may continue to develop cardiovascular, stroke, and kidney diseases. The mechanisms underlying the poorly controlled hypertension remain incompletely understood. Recently, we have focused our efforts to uncover additional renal mechanisms, pathways, and therapeutic targets of poorly controlled hypertension and target organ injury using novel animal models or innovative experimental approaches. Specifically, we studied and elucidated the important roles of intratubular, intracellular, and mitochondrial angiotensin II (Ang II) system in the development of Ang II-dependent hypertension. The objectives of this invited article are to review and discuss our recent findings that (a) circulating and intratubular Ang II is taken up by the proximal tubules via the (AT1) AT1a receptor-dependent mechanism, (b) intracellular administration of Ang II in proximal tubule cells or adenovirus-mediated overexpression of an intracellular Ang II fusion protein selectively in the mitochonria of the proximal tubules induces blood pressure responses, and (c) genetic deletion of AT1 (AT1a) receptors or the Na+/H+ exchanger 3 selectively in the proximal tubules decreases basal blood pressure and attenuates Ang II-induced hypertension. These studies provide a new perspective into the important roles of the intratubular, intracellular, and mitochondrial angiotensin II/AT1 (AT1a) receptor signaling in Ang II-dependent hypertensive kidney diseases.

Correction: Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis.

[This corrects the article DOI: 10.18632/oncotarget.10583.].

In vitro and in vivo imaging of peroxynitrite by a ratiometric boronate-based fluorescent probe.

Peroxynitrite (ONOO-) is an important species involved in many physiopathological processes. Progresses have been made in developing novel fluorescent probes to detect peroxynitrite with relatively high sensitivity and specificity. Herein, we report the synthesis, characterization and biological applications of a new boronate-based fluorescent probe, 4-MB. The studies showed that 4-MB exhibits a dual ratiometric and calorimetric response toward peroxynitrite due to ONOO--triggered oxidative reaction. A possible mechanism of the oxidation reaction was proposed and the reaction product was isolated and characterized using different spectroscopic methods. We have thoroughly demonstrated the utility of 4-MB for intracellular peroxynitrite imaging. Further, we showed that 4-MB can be potentially employed to visualize exogenous and endogenous peroxynitrite in RAW264.7 macrophages, EAhy926 cells, zebrafish and in live tissues from a high-fat diet-induced obese mouse model.

Increased serum levels of betatrophin in pancreatic cancer-associated diabetes.

Long-standing diabetes or glucose intolerance is recognized as a crucial event in the process of pancreatic cancer. Betatrophin, a novel liver-derived hormone, promotes ß-cell proliferation and improves glucose intolerance. However, the relationship between betatrophin and PDAC-associated diabetes is not fully understood. To evaluate the serum betatrophin levels in PDAC-associated diabetes, a total 105 Taiwanese subjects including 15 healthy subjects, and 12 patients having PDAC with normal glucose tolerance (PDAC-NGT), 12 patients having PC with impaired glucose tolerance (PDAC-IGT), and 66 patients having PC with diabetes mellitus (PDAC-DM) were enrolled for this study. Serum betatrophin and carbohydrate antigen 19-9 (CA19-9) levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Compared to healthy subjects, PDAC patients had higher levels of betatrophin and CA19-9. Consistently, betatrophin protein was significantly expressed in pancreatic ductal of PDAC-associated DM patients using immunohistochemistry (IHC) method. Furthermore, multivariate regression analysis showed the betatrophin was significantly and positively independent with T category (ß= 0.605, P=0.010), serum albumin (ß= 0. 423, P=0.021), lipase (ß= 0.292, P=0.039), and blood urea nitrogen (BUN) (ß= 0.303, P=0.040). Further, the betatrophin was three folds of having PDAC-associated diabetes with the highest odds ratio [OR=3.39; 95% CI (1.20-9.57); P=0.021) and receiver operating characteristic (ROC) curve analysis showed that AUC value of betarophin was 0.853 which is slightly larger than AUC value of CA19-9 (0.792) in PDAC-DM patients. Interestingly, AUC value of betarophin plus CA19-9 was 0.988 in PDAC-DM patients. Therefore, betatrophin combined CA19-9 may serve as a potential biomarker for PDAC-associated diabetes.

Higher serum betatrophin level in type 2 diabetes subjects is associated with urinary albumin excretion and renal function.

BACKGROUND: Betatrophin is a newly identified liver-derived hormone that is associated with glucose homeostasis and lipid metabolism. Although dysregulated lipid metabolism results in diabetic nephropathy (DN) development in patients with type 2 diabetes mellitus (T2DM), it is not understood whether betatrophin is associated with urinary albumin excretion and renal function. METHODS: Based on albumin/creatinine ratio (ACR), 109 T2DM patients were divided into normoalbuminuria (ACR <30 mg/g), microalbuminuria (ACR between 30 and 300 mg/g), and macroalbuminuria (ACR > 300 mg/g). Serum betatrophin levels of 109 T2DM patients and 32 healthy subjects were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum level of betatrophin was significantly increased in T2DM patients with normoalbuminuria, microalbuminuria, and macroalbuminuria as compared with healthy subjects (P < 0.001). Serum betatrophin level was positively correlated with sex, duration of diabetes, systolic blood pressure (SBP), body mass index (BMI), ACR, and triglyceride, whereas it was inversely correlated with estimated glomerular filtration rate (eGFR), total cholesterol, and high-density lipoprotein cholesterol (HDL-C) (P < 0.001). Furthermore, multivariate regression analysis showed the betatrophin was significantly and positively independent with triglyceride and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), whereas it was inversely independent with eGFR, total cholesterol, and low-density lipoprotein cholesterol (HDL-C) (P < 0.05). In addition, the betatrophin had higher odds of having DN [odds ratio (OR) = 5.65, 95 % confidence interval (CI) 2.17-14.57, P < 0.001]. CONCLUSION: Betatrophin is significantly increased in T2DM patients with different stages of albuminuria. Betatrophin may be a novel endocrine regulator involved in DN development.

Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis.

Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single-photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer.