Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.

Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

(Pro)renin Receptor Regulates Phosphate Homeostasis in Rats via Releasing Fibroblast Growth Factor-23.

Phosphate (Pi) is one of the basic necessities required for sustenance of life and its metabolism largely relies on excretory function of the kidney, a process chiefly under the endocrine control of bone-derived fibroblast growth factor 23 (FGF23). However, knowledge gap exists in understanding the regulatory loop responsible for eliciting phophaturic response to Pi treatment. Here, we reported a novel role of (pro)renin receptor (PRR) in mediating phosphaturic response to Pi treatment via upregulation of FGF23 production. Male Sprague-Dawley rats were pretreated for 5 days via osmotic pump-driven infusion of a PRR antagonist PRO20 or vehicle, and then treated with high Pi (HP) solution as drinking fluid for the last 24 h. PRO20 reduced HP-induced Pi excretion by 42%, accompanied by blunted upregulation of circulating FGF23 and parathyroid hormone (PTH) and downregulation of renal Na/Pi-IIa expression. In cultured osteoblast cells, exposure to HP induced a 1.56-fold increase in FGF23 expression, which was blunted by PRO20 or siRNA against PRR. Together, these results suggest that activation of PRR promotes phosphaturic response through stimulation of FGF23 production and subsequent downregulation of renal Na/Pi-IIa expression.

Role of (pro)renin receptor in cyclosporin A-induced nephropathy.

Calcineurin inhibitors such as cyclosporin A (CsA) have been widely used to improve graft survival following solid-organ transplantation. However, the clinical use of CsA is often limited by its nephrotoxicity. The present study tested the hypothesis that activation of the (pro)renin receptor (PRR) contributes to CsA-induced nephropathy by activating the renin-angiotensin system (RAS). Renal injury in male Sprague-Dawley rats was induced by a low-salt diet combined with CsA as evidenced by elevated plasma creatinine and blood urea nitrogen levels, decreased creatinine clearance and induced renal inflammation, apoptosis and interstitial fibrosis, and elevated urinary N-acetyl-ß-d-glucosaminidase activity and urinary kidney injury molecule-1 content. Each index of renal injury was attenuated following 2 wk of treatment with the PRR decoy inhibitor PRO20. Although CsA-treated rats with kidney injury displayed increased renal soluble (s)PRR abundance, plasma sPRR, renin activity, angiotensin II, and heightened urinary total prorenin/renin content, RAS activation was attenuated by PRO20. Exposure of cultured human renal proximal tubular HK-2 cells to CsA induced expression of fibronectin and sPRR production, but the fibrotic response was attenuated by PRO20 and siRNA-mediated PRR knockdown. These findings support the hypothesis that activation of PRR contributes to CsA-induced nephropathy by activating the RAS in rats. Of importance, we provide strong proof of concept that targeting PRR offers a novel therapeutic strategy to limit nephrotoxic effects of immunosuppressant drugs.NEW & NOTEWORTHY The present study reports, for the first time, that activation of the (pro)renin receptor drives the renin-angiotensin system to induce renal injury during cyclosporin A administration. More importantly, our study has identified that antagonism with PRO20 offers a novel intervention in the management of side effects of cyclosporin A.

Modeling three-dimensional underwater acoustic propagation over multi-layered fluid seabeds using the equivalent source method.

This paper develops an efficient three-dimensional (3D) underwater acoustic propagation model with multi-layered fluid seabeds based on the equivalent source method (ESM). It solves the Helmholtz equation exactly by a superposition of fields generated by equivalent sources. A linear system coupling ESM equations is derived by imposing boundary conditions and solved iteratively using the generalized minimum residual method. Unlike a direct ESM solver, matrix-vector products in each iteration are evaluated by a pre-corrected fast Fourier transformation (PFFT), significantly reducing the numerical cost and enabling efficient solution of 3D large-scale propagation. Moreover, sound speed profiles can be taken into account by dividing the water column into sub-layers, each of which requires an individual PFFT procedure using an FFT subgrid scheme. Simulations of propagation over a Gaussian canyon validate the PFFT-accelerated ESM (PFFT-ESM). The capability of the PFFT-ESM for 3D scattering problems is demonstrated by further presenting the Gaussian canyon simulations with corrugated surface waves.

Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway.

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear ß-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or ß-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.

Modeling propagation in shallow water with the range-dependent sea surfaces and fluid seabeds using the equivalent source method.

This paper describes a shallow water range-dependent propagation model (RPM) based on the equivalent source method (ESM). The proposed model allows both the sea surface and fluid seabed to vary with the propagation range. The proposed equivalent source method-based range-dependent propagation model (ESM-RPM) utilizes three sets of equivalent sources, placed above the sea surface, below the seabed, and above the seabed, which replace the sea surface reflection, seabed reflection, and seabed transmission, respectively. The unknown strengths of the equivalent sources can be determined by solving an inverse problem based on the boundary conditions. The capability of the ESM-RPM for propagation in refractive water is demonstrated by evaluating the Green's function using a modal projection method. Numerical simulations are conducted in iso-velocity and refractive shallow water with an underwater canyon and corrugated surface waves, including two-dimensional (2-D) propagation across the canyon and three-dimensional (3-D) propagation along the canyon. Further simulations demonstrate the 2-D across-canyon and 3-D along-canyon propagations with random rough sea surfaces. The results show that the proposed ESM-RPM provides efficient, benchmark-quality numerical solutions that accurately capture the mode coupling associated with the varying cross section of the waveguide. Thus, the model has great potential to be applied in benchmarking propagation in shallow water with the varying sea surface and seabed.

Soluble (pro)renin receptor promotes the fibrotic response in renal proximal tubule epithelial cells in vitro via the Akt/ß-catenin/Snail signaling pathway.

Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease. The soluble form of (pro)renin receptor (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, can be detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in the regulation of the fibrotic response in a cultured human renal proximal tubular cell line (HK-2 cells) in the setting of transforming growth factor (TGF)-ß or sPRR-His treatment. The TGF-ß-induced fibrotic response of HK-2 cells was indicated by upregulation of fibronectin (FN) expression; meanwhile, TGF-ß could also induce the generation of sPRR, due to enhanced cleavage of full-length PRR. To explore the role of sPRR in the fibrotic response of HK-2 cells, we blocked the production of sPRR with a the S1P inhibitor PF429242 and found that PF429242 remarkably suppressed TGF-ß-induced sPRR generation and FN expression in HK-2 cells. Administration of sPRR-His restored the PF429242-attenuated FN expression in HK-2 cells, indicating that sPRR could promote the TGF-ß-induced fibrotic response. Furthermore, sPRR-His alone also increased the abundance of FN in HK-2 cells. These data suggested that sPRR was sufficient and necessary for the TGF-ß-induced fibrotic response of HK-2 cells. Mechanistically, sPRR activated the AKT and ß-catenin pathway in HK-2 cells, and blockade of the AKT or ß-catenin pathway significantly abrogated sPRR-induced FN and Snail expression. Taking together, sPRR promoted the fibrotic response of HK-2 cells by activating Akt/ß-catenin/Snail signaling, and it may serve as a potential therapeutic target in renal fibrosis.

Three-dimensional sound scattering from transversely symmetric surface waves in deep and shallow water using the equivalent source method.

This paper proposes a propagation model to calculate the three-dimensional (3-D) sound scattering from transversely symmetric sea surface waves in both deep and shallow water using the equivalent source method (ESM). The 3-D sound field is calculated by integrating an assembly of two-dimensional (2-D) transformed fields with different out-of-plane wavenumbers through a cosine transform. Each 2-D solution is calculated using the ESM incorporating a complex image method that can efficiently and accurately solve the 2-D water/seabed Green's function. The oscillatory cosine integral is accurately calculated using a segmented integral scheme requiring relatively few 2-D solutions, which can be further improved through the use of parallel computation. The model is validated by comparison with a 3-D Helmholtz-Kirchhoff method for deep water and a finite element method for a shallow water wedge with both a fluid and an elastic seabed. The model is as accurate as the finite element approach but more numerically efficient, which enables Monte Carlo simulations to be performed for random rough surfaces in order to study the scattering effects at a reasonable computational cost. Also, 3-D pulse propagation in the shallow water wedge is demonstrated to understand the out-of-plane scattering effects further.

A Novel Real-Valued DOA Algorithm Based on Eigenvalue.

To solve the high complexity of the subspace-based direction-of-arrival (DOA) estimation algorithm, a super-resolution DOA algorithm is built in this paper. However, in this method, matrix decomposition is required for each search angle. Therefore, in this paper, real-valued processing is used to reduce the scanning range by half, which is less effective in algorithm complexity. The super-resolution algorithm mainly uses the conservation of energy. By exploring the relationship between the covariance matrix and its complex conjugate, we constructed the real-valued matrix and introduced a real-valued searching source to make the operation of the matrix real-valued. Finally, the simulation experiments show that the proposed algorithm not only reduces the spectral search range by half but also has a higher angular resolution than the traditional algorithm.