The endocrine basis of the cardio-renal axis: New perspectives regarding corin.

The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor-/-). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.

Novel perspectives regarding the physiologic mechanisms by which gliflozins induce reticulocytosis and erythrocytosis.

Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease.

The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiological pathways that participate in SARS-CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang)-(1-7), in maintaining microcirculatory balance and in the control of activated proinflammatory and procoagulant pathways, generated in this disease, have been largely clarified. The kallikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiological pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiological changes characteristic to this disorder. Herein, we outline the current knowledge regarding the reciprocal interactions of RAAS, BK, and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R, might be explored as potential novel therapeutic strategies in this devastating disorder.

Heparanase in Acute Pancreatitis.

Acute pancreatitis (AP) is one of the most common diseases in gastroenterology, affecting 2% of all hospitalized patients. Nevertheless, neither the etiology nor the pathophysiology of the disease is fully characterized, and no specific or effective treatment has been developed. Heparanase (Hpa) is an endoglycosidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs) into shorter oligosaccharides, activity that is highly implicated in cell invasion associated with cancer metastasis and inflammation. Given that AP is a typical inflammatory disease, we investigated whether Hpa plays a role in AP. Our results provide keen evidence that Hpa expression and activity are significantly increased following cerulein-induced AP in wild type mice. In parallel to the classic manifestations of AP, namely elevation of amylase and lipase levels, pancreas edema and inflammation as well as induction of cytokines and signaling molecules, have been detected in this experimental model of the disease. Noteworthy, these features were far more profound in transgenic mice overexpressing heparanase (Hpa-Tg), suggesting that these mice can be utilized as a model system to reveal the molecular mechanism by which Hpa functions in AP. Further support for the involvement of Hpa in the pathogenesis of AP emerged from our observation that treatment of experimental AP with PG545 or SST0001(= Ronepastat), two potent Hpa inhibitors, markedly attenuated the biochemical, histological and immunological manifestations of the disease. Hpa, therefore, emerges as a potential new target in AP, and Hpa inhibitors are hoped to prove beneficial in AP along with their promising efficacy as anti-cancer compounds.