Identification of natriuretic peptide receptor A-related gene expression signatures in podocytes in vivo reveals baseline control of protective pathways.

Natriuretic peptide receptor-A (NPR-A) is the principal receptor for the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Targeted deletion of NPR-A in mouse glomerular podocytes significantly enhances renal injury in vivo in the DOCA-salt experimental model. It was therefore hypothesized that natriuretic peptides exert a direct protective effect on glomerular barrier integrity through activation of NPR-A and modulation of gene expression patterns in podocytes.

Auto/Paracrine C-Type Natriuretic Peptide/Cyclic GMP Signaling Prevents Endothelial Dysfunction.

Endothelial dysfunction is cause and consequence of cardiovascular diseases. The endothelial hormone C-type natriuretic peptide (CNP) regulates vascular tone and the vascular barrier. Its cGMP-synthesizing guanylyl cyclase-B (GC-B) receptor is expressed in endothelial cells themselves.

Impact of Impaired Kidney Function on Arrhythmia-Promoting Cardiac Ion Channel Regulation.

Chronic kidney disease (CKD) is associated with a significantly increased risk of cardiovascular events and sudden cardiac death. Although arrhythmias are one of the most common causes of sudden cardiac death in CKD patients, the molecular mechanisms involved in the development of arrhythmias are still poorly understood. In this narrative review, therefore, we summarize the current knowledge on the regulation of cardiac ion channels that contribute to arrhythmia in CKD.

Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct.

The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury.

Cardiovascular Risk Factor Control in 70- to 95-Year-Old Individuals: Cross-Sectional Results from the Population-Based AugUR Study.

Cardiovascular risk factors such as high glucose, LDL-cholesterol, blood pressure, and impaired kidney function are particularly frequent in old-aged individuals. However, population-based data on the extent of cardiovascular risk factor control in the old-aged population is limited. AugUR is a cohort of the mobile "70+"-year-old population of/near Regensburg, recruited via population registries.

Localization of natriuretic peptide receptors A, B, and C in healthy and diseased mouse kidneys.

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection.

A single intravenous injection of cyclosporin A-loaded lipid nanocapsules prevents retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy.

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models.

Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative.

An -Package for the Deconvolution and Integration of 1D NMR Data: MetaboDecon1D.

NMR spectroscopy is a widely used method for the detection and quantification of metabolites in complex biological fluids. However, the large number of metabolites present in a biological sample such as urine or plasma leads to considerable signal overlap in one-dimensional NMR spectra, which in turn hampers both signal identification and quantification. As a consequence, we have developed an easy to use -package that allows the fully automated deconvolution of overlapping signals in the underlying Lorentzian line-shapes.

Novel soluble guanylyl cyclase activators increase glomerular cGMP, induce vasodilation and improve blood flow in the murine kidney.

Background And Purpose: Generation of cGMP via NO-sensitive soluble guanylyl cyclase (sGC) has been implicated in the regulation of renal functions. Chronic kidney disease (CKD) is associated with decreased NO bioavailability, increased oxidative stress and oxidation of sGC to its haem-free form, apo-sGC. Apo-sGC cannot be activated by NO, resulting in impaired cGMP signalling that is associated with chronic kidney disease progression.

Heart-Microcirculation Connection: Effects of ANP (Atrial Natriuretic Peptide) on Pericytes Participate in the Acute and Chronic Regulation of Arterial Blood Pressure.

Cardiac ANP (atrial natriuretic peptide) moderates arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve inhibition of the renin-angiotensin-aldosterone system, increased natriuresis, endothelial permeability, and vasodilatation. The contribution of the direct vasodilating effects of ANP to blood pressure homeostasis is controversial because variable levels of the ANP receptor, GC-A (guanylyl cyclase-A), are expressed among vascular beds.

Adenovirus-Mimetic Nanoparticles: Sequential Ligand-Receptor Interplay as a Universal Tool for Enhanced / Cell Identification.

Viral infection patterns often rely on precisely coordinated sequences of distinct ligand-receptor interactions, leading in many cases to an outstanding target cell specificity. A successful mimicry of viral targeting strategies to create more site-specific nanoparticles (NPs) would therefore require particle-cell interactions to also be adequately controllable. In the present study, hetero-multivalent block-copolymer NPs present their attached ligands in a sterically controlled manner to create a sequential NP-cell interaction similar to the cell infiltration strategy of human adenovirus type 2.

Nanoparticles Mimicking Viral Cell Recognition Strategies Are Superior Transporters into Mesangial Cells.

Poor drug availability in the tissue of interest is a frequent cause of therapy failure. While nanotechnology has developed a plethora of nanocarriers for drug transport, their ability to unequivocally identify cells of interest remains moderate. Viruses are the ideal nanosized carriers as they are able to address their embedded nucleic acids with high specificity to their host cells.

Myogenic vasoconstriction requires G/G and LARG to maintain local and systemic vascular resistance.

Myogenic vasoconstriction is an autoregulatory function of small arteries. Recently, G-protein-coupled receptors have been involved in myogenic vasoconstriction, but the downstream signalling mechanisms and the in-vivo-function of this myogenic autoregulation are poorly understood. Here, we show that small arteries from mice with smooth muscle-specific loss of G/G or the Rho guanine nucleotide exchange factor ARHGEF12 have lost myogenic vasoconstriction.

Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage.

Synthesis of renin in renal renin-producing cells (RPCs) is controlled via the intracellular messenger cAMP. Interference with cAMP-mediated signaling by inducible knockout of Gs-alpha (Gsα) in RPCs of adult mice resulted in a complex adverse kidney phenotype. Therein, glomerular endothelial damage was most striking.

Protein Kinase G Is Involved in Acute but Not in Long-Term Regulation of Renin Secretion.

Pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) is, in combination with diuretics, the first-choice treatment for hypertension, although 10-20% of patients do not respond adequately. Next to the RAAS, the nitric oxide/cGMP/protein kinase G (PKG) system is the second fundamental blood pressure regulator. Whether both systems influence each other is not well-studied.

Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes.

Aims: The EMPA-REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca -dependent activation of Ca /calmodulin-dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII- activity and improves Ca -handling in human and murine ventricular myocytes.

The renal vasodilatory effect of prostaglandins is ameliorated in isolated-perfused kidneys of endotoxemic mice.

Endotoxemia-related acute kidney injury (AKI) is associated with increased formation of prostaglandins, which may serve as a compensatory mechanism to maintain renal function. We hypothesized that an increase of renal EP or EP receptors and/or a downregulation of renal EP and EP receptors enhances PGE-induced renal vasodilatation. Injection of lipopolysaccharide (LPS; 3 mg/kg i.

Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure.

Background: Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone, but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (SMCs).

The Mouse Isolated Perfused Kidney Technique.

The mouse isolated perfused kidney (MIPK) is a technique for keeping a mouse kidney under ex vivo conditions perfused and functional for 1 hr. This is a prerequisite for studying the physiology of the isolated organ and for many innovative applications that may be possible in the future, including perfusion decellularization for kidney bioengineering or the administration of anti-rejection or genome-editing drugs in high doses to prime the kidney for transplantation. During the time of the perfusion, the kidney can be manipulated, renal function can be assessed, and various pharmaceuticals administered.

Extracellular K rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl -dependent and independent mechanisms.

Key Points: High dietary potassium (K ) intake dephosphorylates and inactivates the NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Using several ex vivo models, we show that physiological changes in extracellular K , similar to those occurring after a K rich diet, are sufficient to promote a very rapid dephosphorylation of NCC in native DCT cells. Although the increase of NCC phosphorylation upon decreased extracellular K appears to depend on cellular Cl fluxes, the rapid NCC dephosphorylation in response to increased extracellular K is not Cl -dependent.

Single and Transient Ca Peaks in Podocytes do not induce Changes in Glomerular Filtration and Perfusion.

Chronic alterations in calcium (Ca) signalling in podocytes have been shown to cause proteinuria and progressive glomerular diseases. However, it is unclear whether short Ca peaks influence glomerular biology and cause podocyte injury. Here we generated a DREADD (Designer Receptor Exclusively Activated by a Designer Drug) knock-in mouse line to manipulate intracellular Ca levels.