Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: Pathologic implications and putative pharmacologic targets.

Though the pathogenesis of hyperuricemia-induced renal complications is not precisely known, hyperuricemia has been recognized as an independent risk factor for renal disease. While the clinical implication of hyperuricemia in renal disease has been a contemporary topic of debate, growing body of bench and clinical evidences certainly suggest a causative role of high uric acid in renal abnormalities by implicating diverse pathologic and molecular mechanisms. Urate crystals after having deposited in the kidney could cause hyperuricemia nephropathy leading to glomerular hypertrophy and tubulointerstitial fibrosis, while high serum uric acid might predict progressive renal damage and dysfunction. Hyperuricemia could be associated with manifestation of tubular injury and macrophage infiltration as well as an increased expression of inflammatory mediators. This review sheds light on the mechanistic aspects pertaining to hyperuricemia-associated renal abnormalities. Besides, the renal detrimental actions of high uric acid possibly mediated through its potential role on oxidative stress, renal inflammation, endothelial dysfunction, glycocalyx shedding, endothelial-to-mesenchymal transition and more specifically on the renal epithelial-to-mesenchymal transition have been addressed. Moreover, this review discusses a number of potential targets such as endothelin-1, TLR4/NF-kB, PI3K/p-Akt, Wnt5a/Ror2, NLRP3 inflammasome, NADPH oxidase, ERK1/2, enhancer of zeste homolog 2, serum response factor and Smad3/TGF-ß signalling pathways, among others, implicated in hyperuricemia-associated renal abnormalities. This review finally apprises a number of bench and clinical studies which supporting a notion that the pharmacologic reduction of high uric acid might have a therapeutic value in the management of renal abnormalities, with an emphasis on febuxostat and its renal pleiotropic actions.

Molecular targets of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits.

The activation of peroxisome proliferator-activated receptor α (PPARα) is a key pharmacological drug target for dyslipidemic management. Dyslipidemia is associated with abnormal serum lipid profiles viz. elevated total cholesterol, high triglyceride, elevated low-density lipoprotein cholesterol, and reduced high-density lipoprotein cholesterol levels. Fenofibrate, a third-generation fibric acid derivative, is an activator of PPARα indicated for the treatment of mixed dyslipidemia and hypertriglyceridemia in adults. Fenofibrate is considered an important lipid-lowering medication employed in patients afflicted with atherogenic dyslipidemia. Intriguingly, recent bench studies have demonstrated an array of cardiovascular and renal pleiotropic beneficial activities of fenofibrate, besides its foremost lipid-lowering action. The activation of PPARα by fenofibrate could negatively regulate the cardiomyocyte hypertrophy. In addition, fenofibrate has been suggested to have a protective effect against experimental ischemia/reperfusion injury in the myocardium in part via endoplasmic reticulum stress inhibition. Fenofibrate has also been shown to suppress arrhythmias in isolated rat hearts subjected to ischemic/reperfusion-induced cardiac injury. Moreover, in a rat model of metabolic syndrome and myocardial ischemia, fenofibrate therapy has been shown to restore antioxidant protection and improve myocardial insulin resistance. Furthermore, studies have highlighted the pleiotropic vascular endothelial protective and antihypertensive actions of fenofibrate. Interestingly, recent bench studies have demonstrated renoprotective actions of fenofibrate by implicating diverse mechanisms. This review sheds light on the current perspectives and molecular mechanistic aspects pertaining to the cardiovascular pleiotropic actions of fenofibrate. Additionally, the renal pleiotropic actions of fenofibrate by focusing its possible modulatory role on renal fibrosis, inflammation and renal epithelial-to-mesenchymal transition have been enlightened.

Effect of edaravone in diabetes mellitus-induced nephropathy in rats.

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.

A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists.

Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats.

Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin-eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.

Classical and pleiotropic actions of dipyridamole: Not enough light to illuminate the dark tunnel?

Dipyridamole is a platelet inhibitor indicated for the secondary prevention of transient ischemic attack. It inhibits the enzyme phosphodiesterase, elevates cAMP and cGMP levels and prevents platelet aggregation. Dipyridamole inhibits the cellular uptake of adenosine into red blood cells, platelets and endothelial cells that results in increased extracellular availability of adenosine, leading to modulation of cardiovascular function. The antiplatelet action of dipyridamole might offer therapeutic benefits in secondary stroke prevention in combination with aspirin. Inflammation and oxidative stress play an important role in atherosclerosis and thrombosis development, leading to stroke progression. Studies demonstrated anti-inflammatory, anti-oxidant and anti-proliferative actions of dipyridamole. These pleiotropic potentials of dipyridamole might contribute to improved therapeutic outcomes when used with aspirin in preventing secondary stroke. Dipyridamole was documented as a coronary vasodilator 5 decades ago. The therapeutic failure of dipyridamole as a coronary vasodilator is linked with induction of 'coronary steal' phenomenon in which by dilating resistance vessels in non-ischemic zone, dipyridamole diverts the already reduced blood flow away from the area of ischemic myocardium. Dipyridamole at high-dose could cause a marked 'coronary steal' effect. Dipyridamole, however, at low-dose could have a minimal hemodynamic effect. Low-dose dipyridamole treatment has a therapeutic potential in partially preventing diabetes mellitus-induced experimental vascular endothelial and renal abnormalities by enhancing endothelial nitric oxide signals and inducing renovascular reduction of oxidative stress. In spite of plenteous research on dipyridamole's use in clinics, its precise clinical application is still obscure. This review sheds lights on pleiotropic pharmacological actions and therapeutic potentials of dipyridamole.

Dapagliflozin: glucuretic action and beyond.

Diabetes mellitus is a greatly challenging disease of the 21 century, and the mortality rate due to this insidious disease is increasing worldwide in spite of availability of effective oral hypoglycemic agents. Satisfactory management of glycemic control in patients afflicted with type 2 diabetes mellitus (T2DM) remains a major clinical challenge. Identification of potential pharmacological target sites is therefore continuing as an integral part of the diabetic research. The sodium-glucose co-transporter type 2 (SGLT2) expressed in the renal proximal tubule plays an essential role in glucose reabsorption. Pharmacological blockade of SGLT2 prevents glucose reabsorption and subsequently induces the elimination of filtered glucose via urine, the process is known as 'glucuresis'. Dapagliflozin is a selective inhibitor of SGLT2. The US FDA approved dapagliflozin in January 2014 to improve glycemic control along with diet and exercise in adult patients afflicted with T2DM. It has a potential to decrease glycated hemoglobin and to promote weight loss. Although the mechanism of action of dapagliflozin is not directly linked with insulin or insulin sensitivity, reduction of plasma glucose by dapagliflozin via induction of glucosuria could improve muscle insulin sensitivity. Moreover, dapagliflozin could cause diuresis and subsequently fall in blood pressure. In addition to general discussion on the pharmacology of dapagliflozin, we propose in this review the possibilities of dual antidiabetic effect of dapagliflozin and its possible additional beneficial actions in hypertensive-obese-T2DM patients through its indirect blood pressure-lowering action and reduction of body calories and weight. Long-term clinical studies are however needed to clarify this contention.

Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials.

Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system.