STING inhibition alleviates experimental peritoneal damage: potential therapeutic relevance for peritoneal dialysis.

Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration failure and, ultimately, discontinuation of PD. Investigation of the molecular mechanisms underlying this damage is essential for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients.

Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy.

: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI.

CCN2 Activates Cellular Senescence Leading to Kidney Fibrosis in Folic Acid-Induced Experimental Nephropathy.

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence.

Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent.

Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis.

Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown.

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system.

Regulated necrosis role in inflammation and repair in acute kidney injury.

Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition.

B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.

Background: In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown.

Methods: CKD patients from the NEFRONA study were used.

STING1 deficiency ameliorates immune-mediated crescentic glomerulonephritis in mice.

Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN.

CCN2 Activates RIPK3, NLRP3 Inflammasome, and NRF2/Oxidative Pathways Linked to Kidney Inflammation.

Inflammation is a key characteristic of both acute and chronic kidney diseases. Preclinical data suggest the involvement of the NLRP3/Inflammasome, receptor-interacting protein kinase-3 (RIPK3), and NRF2/oxidative pathways in the regulation of kidney inflammation. Cellular communication network factor 2 (CCN2, also called CTGF in the past) is an established fibrotic biomarker and a well-known mediator of kidney damage.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition.

BET Protein Inhibitor JQ1 Modulates Mitochondrial Dysfunction and Oxidative Stress Induced by Chronic Kidney Disease.

Among the mechanisms involved in the progression of kidney disease, mitochondrial dysfunction has special relevance. Epigenetic drugs such as inhibitors of extra-terminal domain proteins (iBET) have shown beneficial effects in experimental kidney disease, mainly by inhibiting proliferative and inflammatory responses. The impact of iBET on mitochondrial damage was explored in in vitro studies in renal cells stimulated with TGF-β1 and in vivo in murine unilateral ureteral obstruction (UUO) model of progressive kidney damage.

Mitochondrial Dysfunction in the Cardio-Renal Axis.

Cardiovascular disease (CVD) frequently complicates chronic kidney disease (CKD). The risk of all-cause mortality increases from 20% to 500% in patients who suffer both conditions; this is referred to as the so-called cardio-renal syndrome (CRS). Preclinical studies have described the key role of mitochondrial dysfunction in cardiovascular and renal diseases, suggesting that maintaining mitochondrial homeostasis is a promising therapeutic strategy for CRS.

Vitamin D, Cellular Senescence and Chronic Kidney Diseases: What Is Missing in the Equation?

As life expectancy increases in many countries, the prevalence of age-related diseases also rises. Among these conditions, chronic kidney disease is predicted to become the second cause of death in some countries before the end of the century. An important problem with kidney diseases is the lack of biomarkers to detect early damage or to predict the progression to renal failure.

Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis.

Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease.

Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease.

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients.

Targeting inflammation to treat diabetic kidney disease: the road to 2030.

Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016.

Role of Toll-like receptor 4 in intravascular hemolysis-mediated injury.

Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown.

The Increase in FGF23 Induced by Calcium Is Partially Dependent on Vitamin D Signaling.

Background: Increased FGF23 levels are an early pathological feature in chronic kidney disease (CKD), causing increased cardiovascular risk. The regulation of FGF23 expression is complex and not completely understood. Thus, Ca has been shown to induce an increase in FGF23 expression, but whether that increase is mediated by simultaneous changes in parathyroid hormone (PTH) and/or vitamin D is not fully known.

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis.

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools.

CCN2 Binds to Tubular Epithelial Cells in the Kidney.

Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR).

Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney.

Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non-invasive biomarkers to detect early kidney damage and the onset of a senescent phenotype are lacking. Most of the preclinical senescence studies in aging have been done in very old mice.

Molecular Mechanisms of Kidney Injury and Repair.

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms.

CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation.

Background: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood.

Methods: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible <i>Ccn2</i>-deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta.

CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation.

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor β (TGF-β). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-β together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet.