Effects and regulation of ACE2 and TMPRSS2 abundance in healthy humans and in patients with SARS-CoV-2.

The present narrative review focuses on organ distribution, co-localization, age-, and sex-dependent changes in angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) and how such changes associate with SARS-CoV-2 virus entry and disease severity in humans. ACE2 is a membrane-bound enzyme with lower abundance in children/young adults compared with elderly, with no protein abundance difference between ages 35-50 and >80 but higher in females at reproductive age. ACE2 locates predominantly in gastrointestinal (GI)-tract epithelia, kidney proximal tubules, male and female reproductive organs with very low levels in the lungs.

Diurnal Urinary Aldosterone Excretion and Potassium Intake During Pregnancy Are Associated With High Normal Blood Pressure in Early Childhood.

Background: Offspring blood pressure (OBP) may be programmed during pregnancy. Accordingly, maternal third-trimester 24-hour urine aldosterone levels are associated with fetoplacental trophic effects. Furthermore, high potassium and low sodium intakes are generally recommended in adults with normal renal function.

Renal Ghrelin-Family GPR39 Receptor and Urinary Concentrating Ability.

Key Points: This study provides the first functional documentation of the ghrelin receptor family member GPR39 in the kidney. GPR39 activation directly reduced the urine concentrating capacity by reducing the AVP-induced water permeability of the collecting duct. In parallel, GPR39 activation increased the K excretion through a specific reduction of phosphorylated Na-Cl cotransporter in the distal convoluted tubule.

Soluble guanylate cyclase as a direct target for pharmacologic mitigation of chronic kidney disease.

In a preclinical rat study, Lichtenberger et al. show that BAY-60-2770, a drug that activates soluble guanylyl cyclase, often rendered inactive by oxidative stress, mitigates kidney inflammation, injury, and fibrosis, likely by vascular effects after ischemia-reperfusion. Kidney perfusion, overall vascular reactivity, and medullary microvascular diameter are improved by the drug at doses that do not alter blood pressure.

Low-intensity extracorporeal shockwave therapy in patients with diabetic kidney disease: a matched cohort study.

Purpose: Low-intensity extracorporeal shockwave therapy (LI-ESWT) is a potential novel treatment against diabetic kidney disease (DKD). The present study investigates the longer term effects of LI-ESWT on kidney function in patients with DKD.

Methods: This matched cohort study included 28 patients with DKD, who received six sessions of LI-ESWT.

ACE2 and TMPRSS2 in human kidney tissue and urine extracellular vesicles with age, sex, and COVID-19.

SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex.

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.

Smooth muscle-specific deletion of cellular communication network factor 2 causes severe aorta malformation and atherosclerosis.

Aims: Cellular communication network factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis.

Methods And Results: Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidaemic conditions.

Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension.

MFAP4-Deficiency Aggravates Age-Induced Changes in Resistance Artery Structure, While Ameliorating Hypertension.

Background: Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening.

Effect of dapagliflozin on collectins and complement activation in plasma from patients with type 2 diabetes and albuminuria: Data from the DapKid cohort.

Background: Sodium-glucose cotransporter 2 (SGLT- 2) inhibitors exert cardiovascular and kidney-protective effects in people with diabetes. Attenuation of inflammation could be important for systemic protection. The lectin pathway of complement system activation is linked to diabetic nephropathy.

Effect of Spironolactone on Kidney Function in Kidney Transplant Recipients (the SPIREN trial): A Randomized Placebo-Controlled Clinical Trial.

Key Points: Spironolactone is safe for kidney transplant patients. Spironolactone reduces kidney function by an acute effect, whereafter it remains stable. Spironolactone does not affect the progression of interstitial fibrosis in protocol biopsies.

Effect of short-term changes in salt intake on plasma cytokines in women with healthy and hypertensive pregnancies.

Background: Salt (NaCl) promotes T-lymphocyte conversion to pro-inflammatory Th-17 cells in vitro. Interleukin (IL)-17A aggravates hypertension in preeclampsia (PE) models.

Objectives: It was hypothesized that 1) women with PE exhibit increased plasma IL-17A and related cytokines and 2) high dietary salt intake elevates circulating IL-17A in patients with PE compared to women with healthy pregnancy (HP) and non-pregnant (NonP) women.

Histamine H-receptor antagonism improves conduit artery endothelial function and reduces plasma aldosterone level without lowering arterial blood pressure in angiotensin II-hypertensive mice.

Aldosterone through the mineralocorticoid receptor MR has detrimental effects on cardiovascular disease. It reduces the bioavailability of nitric oxide and impairs endothelium-dependent vasodilatation. In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H receptors.

Nitric oxide, endothelium-derived hyperpolarizing factor, and smooth muscle-dependent mechanisms contribute to magnesium-dependent vascular relaxation in mouse arteries.

Aim: Magnesium (Mg ) is a vasorelaxant. The underlying physiological mechanisms driving this vasorelaxation remain unclear. Studies were designed to test the hypothesis that multiple signaling pathways including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in endothelial cells as well as Ca antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg -dependent vessel relaxation.

Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria.

Significance Statement: Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added.

Effect of controlled hypotensive hemorrhage on plasma sodium levels in anesthetized pigs: An exploratory study.

Perioperative hyponatremia, due to non-osmotic release of the antidiuretic hormone arginine vasopressin, is a serious electrolyte disorder observed in connection with many types of surgery. Since blood loss during surgery contributes to the pathogenesis of hyponatremia, we explored the effect of bleeding on plasma sodium using a controlled hypotensive hemorrhage pig model. After 30-min baseline period, hemorrhage was induced by aspiration of blood during 30 min at mean arterial pressure <50 mmHg.

Amiloride evokes significant natriuresis and weight loss in kidney transplant recipients with and without albuminuria.

Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial Na channel (ENaC). The present nonrandomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin-to-creatinine ratio > 300 mg/g, = 7, and <30 mg/g, = 7, respectively) were included and ingested a diet with fixed Na content (150 mmol/day) for 5 days.

Exploration of complement split products in plasma and urine as biomarkers of kidney graft rejection.

Introduction: The complement system, consisting of more than thirty different soluble and cell-bound proteins, exerts essential functions both in the innate and adaptive immune systems and is believed to be an important contributor to allograft injury in kidney transplantation. The anaphylatoxins C3a and C5a are powerful chemoattractants, recruiting immune effector cells toward the site of complement activation and enhance T-cell response, while C3dg binding to CR2 on B-cells, enhances B-cell immunity at several stages of the B-cell differentiation. Complement split products in plasma and urine could reflect ongoing inflammation and tissue injury.

Low-Intensity Extracorporeal Shockwave Therapy (LI-ESWT) in Renal Diseases: A Review of Animal and Human Studies.

Background: Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues. Application of LI-ESWT in chronic progressive renal diseases is a novel area.