The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

Background: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored.

Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle.

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline.

Aim: The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting.

Renal tissue Po sensing during acute hemodilution is dependent on the diluent.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery.

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction.

Background And Aims: Sodium-glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions.

Impaired SIRT1 activity leads to diminution in glomerular endowment without accelerating age-associated GFR decline.

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age.

Empagliflozin Improves Diastolic Function in a Nondiabetic Rodent Model of Heart Failure With Preserved Ejection Fraction.

Recent studies send an unambiguous signal that the class of agents known as sodium-glucose-linked co-transporter-2 inhibitors (SGLT2i) prevent heart failure hospitalization in patients with type 2 diabetes. However, the mechanisms remain unclear. Herein the authors utilize a rodent model of heart failure with preserved ejection fraction (HFpEF), and demonstrate that treatment with the SGLT2i empagliflozin, reduces left ventricular mass, improving both wall stress and diastolic function.

Reversing CXCL10 Deficiency Ameliorates Kidney Disease in Diabetic Mice.

The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis.

SIRT1 activation attenuates α cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice.

The NAD-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks.

Dual inhibition of sodium-glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction.

Background: Inhibiting both type 1 and 2 sodium-glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart.

Sirtuin 1 activation attenuates cardiac fibrosis in a rodent pressure overload model by modifying Smad2/3 transactivation.

Aims: Transforming growth factor β1 (TGF-β1) is a prosclerotic cytokine involved in cardiac remodelling leading to heart failure (HF). Acetylation/de-acetylation of specific lysine residues in Smad2/3 has been shown to regulate TGF-β signalling by altering its transcriptional activity. Recently, the lysine de-acetylase sirtuin 1 (SIRT1) has been shown to have a cardioprotective effect; however, SIRT1 expression and activity are paradoxically reduced in HF.

Suppression of NLRP3 Inflammasome Activation Ameliorates Chronic Kidney Disease-Induced Cardiac Fibrosis and Diastolic Dysfunction.

Cardiac fibrosis is a common finding in patients with chronic kidney disease. Here, we investigate the cardio-renal effects of theracurmin, a novel formulation of the polyphenolic compound curcumin, in a rat model of chronic kidney disease. Briefly, Sprague-Dawley rats were randomized to undergo sham or subtotal nephrectomy (SNx) surgery.

Sirtuin 1 Activation Reduces Transforming Growth Factor-β1-Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease.

Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor β (TGF-β), is thought to play a pivotal role. With the recent understanding that TGF-β's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-β1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity.

Progenitor cell secretory products exert additive renoprotective effects when combined with ace inhibitors in experimental CKD.

Hypothesis/introduction: Renal fibrovascular injury often persists in chronic kidney disease patients treated with renin-angiotensin system blockers. Intriguingly, early outgrowth cell-derived factor infusion also inhibits chronic renal injury. We sought to determine whether early outgrowth cell-derived factor administration provides further renoprotection when added to renin-angiotensin system blockade.

Recombinant N-Terminal Slit2 Inhibits TGF-β-Induced Fibroblast Activation and Renal Fibrosis.

Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-β Here, we examined whether Slit2 also controls TGF-β-induced renal fibrosis.

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms.

Discovery of common pathways that mediate both pancreatic β-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I2 (IP) receptor in pancreatic β-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3',5'-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 β-cells.

Conditioned Medium from Early-Outgrowth Bone Marrow Cells Is Retinal Protective in Experimental Model of Diabetes.

Bone marrow-derived cells were demonstrated to improve organ function, but the lack of cell retention within injured organs suggests that the protective effects are due to factors released by the cells. Herein, we tested cell therapy using early outgrowth cells (EOCs) or their conditioned media (CM) to protect the retina of diabetic animal models (type 1 and type 2) and assessed the mechanisms by in vitro study. Control and diabetic (db/db) mice (8 weeks of age) were randomized to receive a unique intravenous injection of 5×105EOCs or 0.

Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease.

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial.

Repeated treatment with bone marrow cell secretory products maintains long-term renoprotection in experimental chronic kidney disease: a placebo-controlled trial.

Background: Bone marrow-derived early outgrowth cells (EOCs) secrete soluble factors that exert potent renoprotective effects, such that infusion of their conditioned medium recapitulates the affects of the cells themselves.

Objectives: The objective of this study is to test whether the protective effect of conditioned medium infusion wanes with time and whether tachyphylaxis occurs with repeated administration.

Design: This is a placebo-controlled animal study.

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes.

Epigenetic regulation of oxidative stress is emerging as a critical mediator of diabetic nephropathy. In diabetes, oxidative damage occurs when there is an imbalance between reactive oxygen species generation and enzymatic antioxidant repair. Here, we investigated the function of the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) in attenuating oxidative injury in podocytes, focusing on its regulation of the endogenous antioxidant inhibitor thioredoxin interacting protein (TxnIP).

Application of Modular Therapy for Renoprotection in Experimental Chronic Kidney Disease.

Cell-based regenerative therapies offer a new alternative approach to the treatment of chronic disease. Specifically, studies by our laboratory and others have shown that a subpopulation of cells derived from the bone marrow, known as early outgrowth cells (EOCs), are able to attenuate the progression of chronic kidney disease (CKD). In this study we examined the efficacy of a tissue engineering system, in which EOCs were embedded into submillimeter-sized collagen cylinders.

Dipeptidyl peptidase-4 inhibition improves cardiac function in experimental myocardial infarction: Role of stromal cell-derived factor-1α.

Background: In addition to degrading glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4) inactivates several chemokines, including stromal cell-derived factor-1α (SDF-1α), a pro-angiogenic and cardiomyocyte protective protein. We hypothesized that DPP-4 inhibition may confer benefit following myocardial infarction (MI) in the diabetic setting as a consequence of enhanced SDF-1α availability rather than potentiating GLP-1. To test this we compared the effects of saxagliptin with those of liraglutide and used the SDF-1α receptor (CXCR4) antagonist plerixafor.

SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes.

Aims/hypothesis: Nutrient overabundance and diminished physical activity underlie the epidemic of obesity and its consequences of insulin resistance and type 2 diabetes. These same phenomena, obesity and insulin resistance, are also observed in mammals as they ready themselves for the nutrient deprivation of winter, yet their plasma glucose does not rise. Given the role of silent information regulator 2 (Sir2) and its mammalian orthologue, Sirt1, in survival and life extension during energy deprivation, we hypothesised that enhancing its activity may reduce the insensible energy loss engendered by hyperglycaemia and glycosuria.

CXCR4 promotes renal tubular cell survival in male diabetic rats: implications for ligand inactivation in the human kidney.

Binding of the receptor CXCR4 to its ligand stromal cell-derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death.

Impaired cardiac anti-oxidant activity in diabetes: human and correlative experimental studies.

Increased reactive oxygen species (ROS) are traditionally viewed as arising from the metabolic flux of diabetes, although reduction in the activity of anti-oxidant systems has also been implicated. Among the latter is the major thiol reducing thioredoxin system, the activity of which may be diminished by high glucose-induced expression of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We assessed TxnIP mRNA/protein expression along with thioredoxin activity in human right atrial biopsy specimens from subjects with and without diabetes undergoing coronary artery grafting.