Targeting p66Shc to restore K channel and renal microvascular responses in a preclinical model of diabetic nephropathy.

Renal microvascular injury occurs in most patients with diabetes, representing one of the main causes underlying chronic kidney disease development. We have previously published that overexpression of adaptor protein p66Shc is implicated in the loss of renal microvascular reactivity in rats with diabetic nephropathy (DN) induced by injection of streptozotocin (STZ). Since sulfur heteroarotinoid A2 (SHetA2) is known to interfere with p66Shc signaling, we tested whether SHetA2 would restore renal microvascular reactivity and mitigate kidney injury in our rat model of DN.

Transforming growth factor β receptor 1 and mitogen-activated protein 4 kinase 4 dual inhibitor, TK-850, reduces renal fibrosis in unilateral ureteral-obstructed mice.

Renal fibrosis is a common progression from chronic kidney disease to end-stage renal disease, and its causes are multifactorial. Effective treatment for renal fibrosis requires strategies that address various molecular mechanisms simultaneously. In this study, we investigated the preventive and interventional anti-fibrotic effects of TK-850, a novel dual inhibitor of transforming growth factor-β receptor (TGF-βR)1 and mitogen-activated protein 4 kinase (MAP4K)4.

Synthetic Epoxyeicosatrienoic Acid Mimics Protect Mesangial Cells from Sorafenib-Induced Cell Death.

Nineteen potential mimics of 8,9-epoxyeicosatrienoic acid (8,9-EET), a natural bioactive oxylipin, were synthesized and evaluated for their ability to protect renal mesangial cells against sorafenib-induced cell death in a water-soluble tetrazolium (WST-8) assay. All compounds were also evaluated as inhibitors of soluble epoxide hydrolase. As expected of a potent pan-kinase inhibitor the drug sorafenib caused a significant decrease in cell viability in HRMCs.

Prevention of hypertension-induced renal vascular dysfunction through a p66Shc-targeted mechanism.

Renal microvascular injury occurs in most patients with hypertension-induced nephropathy (HN). We have shown that overexpression of adaptor protein p66Shc is implicated in the loss of renal microvascular reactivity in hypertensive rats. Since sulfur heteroarotinoid A2 (SHetA2) modulates p66Shc, we tested whether SHetA2 would restore renal microvascular reactivity and mitigate kidney injury in a rat HN model.

Correction: Maranto et al. Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo. 2020, , 3412.

In the original publication [...

Hypertension: A Continuing Public Healthcare Issue.

Hypertension is a cardiovascular disease defined by an elevated systemic blood pressure. This devastating disease afflicts 30-40% of the adult population worldwide. The disease burden for hypertension is great, and it greatly increases the risk of cardiovascular morbidity and mortality.

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats.

All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease.

Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis.

Introduction: Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model.

Methods: Male mice went through either UUO or sham surgery.

Kidney Injury by Unilateral Ureteral Obstruction in Mice Lacks Sex Differences.

Introduction: Renal fibrosis is a critical event in the development and progression of chronic kidney disease (CKD), and it is considered the final common pathway for all types of CKD. The prevalence of CKD is higher in females; however, males have a greater prevalence of end-stage renal disease. In addition, low birth weight and low nephron number are associated with increased risk for CKD.

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension.

Hypertension characterized by an elevated blood pressure is a cardiovascular disease that afflicts greater than one in every three adults worldwide. Nuclear receptors are large superfamily of DNA-binding transcription factors that target genes to regulate metabolic and cardiovascular function. Drugs have been developed for nuclear receptors such as peroxisome proliferator-activated receptors (PPARα and PPARγ) and farnesoid X receptor (FXR).

Bioactive lipids in hypertension.

Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction.

Salt-sensitive hypertension after reversal of unilateral ureteral obstruction.

The incidence of ureter obstruction is increasing and patients recovering from this kidney injury often progress to chronic kidney injury. There is evidence that a long-term consequence of recovery from ureter obstruction is an increased risk for salt-sensitive hypertension. A reversal unilateral ureteral obstruction (RUUO) model was used to study long-term kidney injury and salt-sensitive hypertension.

Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression.

Multi-Target Drugs for Kidney Diseases.

Kidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets.

SARS-CoV-2 spike protein causes cardiovascular disease independent of viral infection.

The SARS-CoV-2 virus that results in COVID-19 has been found to damage multiple organs beyond the lung. Interestingly, the SARS-CoV-2 spike (S) protein can be found circulating in the blood of COVID-19 patients. Experimental findings are demonstrating that the circulating S protein can bind to receptors resulting in inflammation and cell, tissue, and organ damage.

Epoxyeicosatrienoic Acid Analog and 20-HETE Antagonist Combination Prevent Hypertension Development in Spontaneously Hypertensive Rats.

Numerous studies indicate a significant role for cytochrome P-450-dependent arachidonic acid metabolites in blood pressure regulation, vascular tone, and control of renal function. Epoxyeicosatrienoic acids (EETs) exhibit a spectrum of beneficial effects, such as vasodilatory activity and anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that inhibits sodium reabsorption in the kidney.

Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath.

Introduction: In COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB ≫ PGE > PGD in the lungs, and 11-dehydro-TxB, a TxA metabolite, in the systemic circulation. While TxA stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA/TP and PGD/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization.

Dual sEH/COX-2 Inhibition Using PTUPB-A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity.

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects.

Epoxylipids and soluble epoxide hydrolase in heart diseases.

Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases.

Kidney in the net of acute and long-haul coronavirus disease 2019: a potential role for lipid mediators in causing renal injury and fibrosis.

Purpose Of Review: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches.

Recent Findings: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps.