Elevated serum PAR-1 levels as an emerging biomarker of inflammation to predict the dengue infection severity.

The present study was designed to check the serum levels of protease-activated receptor (PAR-1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR-1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto-analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and PAR-1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF-α, IL-6, and IL-17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR-1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR-1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR-1 levels can be used as a diagnostic marker for assessing dengue severity.

Wnt/ß-catenin inhibitor pyrivinium attenuates cisplatin-induced acute kidney injury by possibly reducing platinum uptake and accumulation mediated by reduced organic cation transporter-2 expressions.

Aberrant activation of Wnt/ß-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/ß-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the ß-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/ß-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.

Platelet-rich plasma exhibits anti-inflammatory effect and attenuates cardiomyocyte damage by reducing NF-κB and enhancing VEGF expression in isoproterenol induced cardiotoxicity model.

The present study investigated the cardioprotective effects of activated platelet-rich plasma (PRP) on high dose isoproterenol (ISO) induced cardiotoxicity. ISO was injected at a dose of 85 mg/kg/day, s.c. for 2 days. Cardiac function parameters including dp/dt max/min, left ventricular end diastolic pressure (LVEDP), relaxation constant (tau) and electrocardiogram (ECG) changes, anti-oxidant and membrane bound enzymes assays, pro-inflammatory cytokine levels, collagen content, immunohistochemical staining/gene expression of vascular endothelial growth factor (VEGF), cTnI (cardiac troponin I), NF-κB (nuclear factor kappa B), Smad-2/3, TGF-ß (transforming growth factor), collagen-1/3 proteins were evaluated. PRP and platelet-poor plasma (PPP) were injected intramyocardially (200 µl in each ventricle region) 3 h after first dose of ISO under anesthesia. ISO injection induced cardiac dysfunction, hypertrophy, fibrosis, necrosis due to decline in anti-oxidant capacity, enhanced NF-κB and reduced cTnI immunostaining. However, the PRP injection attenuated these cardiac pathological changes by exerting anti-inflammatory properties and promoting cardiomyocyte repair.

Pathological role of the calcium-sensing receptor in sepsis-induced hypotensive shock: Therapeutic possibilities and unanswered questions.

Sepsis is a life-threatening disease involving multiorgan dysfunction, prompted by an unregulated host response to infection. Shock is a complication of sepsis in which the circulatory and cellular metabolism anomalies are significant enough to raise the risk of death. Calcium dyshomeostasis occurs during sepsis condition due to imbalance between calcium uptake and excessive release induced by inflammatory cytokines. This calcium imbalance can cause activation of calcium-sensing receptors (CaSRs) located on the surface of T cells and thereby promote release of reactive oxygen species (ROS). The elevated ROS and inflammatory cytokines during sepsis condition have been reported to directly damage the endothelial cells, disrupt the barrier functions that might result in leakage of fluids, and inflammatory cells in tissues Moreover, several evidence have revealed that the calcium mediated activation of CaSR could produce systemic vasodilatory response by stimulating the nitric oxide production and opening of calcium-activated potassium channels, while infusion of its antagonist elevated the blood pressure. These evidence indicate that activation of CaSR during sepsis conditions results in release of ROS and inflammatory cytokines, which could produce an endothelial barrier damage, cardiomyocyte apoptosis. These pathological events could produce loss of fluid in tissues and cardiac dysfunction. Further the direct vasodilatory effects of CaSR activation might add to the shock-like condition. Thus, we hereby propose that inhibition of CaSR could suppress the release of ROS, inflammatory mediators, and thereby prevent the endothelial damage, cardiac dysfunction, and maintain systemic vascular tone.

Serum protease-activated receptor (PAR-1) levels as a potential biomarker for diagnosis of inflammation in type 2 diabetic patients.

BACKGROUND: Inflammation is a prominent clinical manifestation in type 2 diabetes mellitus (T2DM) patients, often associated with insulin resistance, metabolic dysregulation, and other complications. AIM OF THE STUDY: The present study has been designed to check the serum levels of PAR-1 and correlate with various clinical manifestations and inflammatory cytokines levels in type 2 diabetic subjects. MATERIAL AND METHODS: The study population was divided into two groups, healthy volunteers (n = 15): normal glycated hemoglobin (HbA1c) (4.26 ± 0.55) and type 2 diabetic subjects (n = 30): HbA1c levels (7.80 ± 2.41). The serum levels of PAR-1 (ELISA method) were studied in both groups and correlated with demographic parameters age, weight, body mass index (BMI), and conventional inflammation biomarkers like C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumour necrosis factor-alpha (TNF-α). RESULTS: The demographic variables including the body weight (77.38 ± 10.00 vs. controls 55.26 ± 6.99), BMI (29.39 ± 3.61 vs. controls 25.25 ± 4.01), glycemic index HbA1c (7.80 ± 2.41 vs. controls 4.26 ± 0.55) were found to be statistically increased in T2DM subjects than the healthy control group. The levels of various inflammatory biomarkers and PAR-1 were significantly elevated in T2DM groups in comparison to healthy volunteers. The univariate and multivariate regression analysis revealed that elevated PAR-1 levels positively correlated with increased body weight, BMI, HbA1c, and inflammatory cytokines. CONCLUSION: Our findings indicate that the elevated serum PAR-1 levels serve as an independent predictor of inflammation in T2DM subjects and might have prognostic value for determining T2DM progression.

Evolution of ß-catenin-independent Wnt-GSK3-mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model.

OBJECTIVE: Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event's revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/ß-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases. METHOD: Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3ß mediator. RESULT: The GSK-3ß could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3ß by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents. CONCLUSION: We hereby discuss a novel therapeutic role of the ß-catenin independent, Wnt-GSK3-mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.

Calcium sensing receptor as a novel target for treatment of sepsis induced cardio-renal syndrome: Need for exploring mechanisms.

Calcium sensing receptor (CaSR) is localized in various organs and plays diverse physiological and pathological roles. Several scientific contributions have suggested the involvement of this cell surface receptor in cardiac and renal diseases. Sepsis is considered to be one of the major causes of ICU admissions. Cardiac dysfunction and acute kidney injury are major manifestations of sepsis and associated with reduced survival. Presently, the treatment approaches for management of sepsis induced cardiac depression and kidney injury are not satisfactory. Activation of CaSR has been demonstrated to induce cardiomyocyte damage upon lipopolysaccaharde (LPS) exposure by enhancing calcium ion levels, ROS (reactive oxygen species) production, promotion of inflammation and apoptosis. In addition, CaSR seems to be a critical regulator of intracellular calcium ion levels, which is directly implicated in induction of mitochondrial dysfunction and release of various pro-apoptotic pathways during sepsis. Certain evidences have also documented the expression of CaSR on neutrophils and T lymphocytes, where it is involved in activation of neutrophils and induces apoptosis of immune cells. Moreover, the expression of CaSR has been confirmed in podocytes, mesangial cells, proximal tubular cells and its activation is responsible for podocyte effacement, mesangial cell proliferation and proximal tubular cell apoptosis. We have analyzed the existing evidences, and critically discussed the possible mechanisms underlying CaSR activation mediated cardiac and renal dysfunction in sepsis condition.

Rat Model of Isoproterenol-Induced Myocardial Injury.

Isoproterenol (ISO) administration produces significant biochemical and histological changes including oxidative stress, reactive oxygen species (ROS) overproduction, and inflammation that leads to aggravation of myocardial injury. Subcutaneous or intraperitoneal ISO injection into rats can replicate several features of human heart disease, making it a useful tool for comprehending the underlying mechanisms and evaluating potential therapeutic strategies. In the present chapter, we elaborate on how depending on the precise experimental goals and the intended level of severity, different dosages and regimens are employed to induce myocardial injury.

Radiopharmaceuticals: navigating the frontier of precision medicine and therapeutic innovation.

This review article explores the dynamic field of radiopharmaceuticals, where innovative developments arise from combining radioisotopes and pharmaceuticals, opening up exciting therapeutic possibilities. The in-depth exploration covers targeted drug delivery, delving into passive targeting through enhanced permeability and retention, as well as active targeting using ligand-receptor strategies. The article also discusses stimulus-responsive release systems, which orchestrate controlled release, enhancing precision and therapeutic effectiveness. A significant focus is placed on the crucial role of radiopharmaceuticals in medical imaging and theranostics, highlighting their contribution to diagnostic accuracy and image-guided curative interventions. The review emphasizes safety considerations and strategies for mitigating side effects, providing valuable insights into addressing challenges and achieving precise drug delivery. Looking ahead, the article discusses nanoparticle formulations as cutting-edge innovations in next-generation radiopharmaceuticals, showcasing their potential applications. Real-world examples are presented through case studies, including the use of radiolabelled antibodies for solid tumors, peptide receptor radionuclide therapy for neuroendocrine tumors, and the intricate management of bone metastases. The concluding perspective envisions the future trajectory of radiopharmaceuticals, anticipating a harmonious integration of precision medicine and artificial intelligence. This vision foresees an era where therapeutic precision aligns seamlessly with scientific advancements, ushering in a new epoch marked by the fusion of therapeutic resonance and visionary progress.

Do COVID-19 viral infection and its mRNA vaccine carry an equivalent risk of myocarditis? Review of the current evidence, insights, and future directions.

According to recent epidemiological analysis, the percentage of world population infected with COVID-19 by end of December 2020 is approximately 12.56%1. COVID induced acute care and ICU hospitalization rates are around 9.22 (95% CI: 18.73-19.51), and 4.14 (95% CI: 4.10-4.18) per 1000 population1. Although therapeutic strategies such as antivirals, intravenous immunoglobulins and corticosteroids have shown modest efficacy in reducing the disease progression, they are not disease specific and only temper the immune mediated attack on the systemic tissues. Therefore, clinicians started to rely on mRNA COVID-19 vaccines, which are clinically efficacious in reducing the incidence, disease severity and systemic complications of COVID-19 infections. Nevertheless, usage of COVID-19 mRNA vaccines is also associated with cardiovascular complications such as myocarditis and pericarditis. On the other hand, COVID-19 infections itself are associated with cardiovascular complications such as myocarditis. The underlying signaling pathways for occurrence of COVID-19 and mRNA COVID-19 vaccine induced myocarditis are quite different although there is some overlap in autoimmunity and cross reactivity mechanisms. With media reports highlighting the cardiovascular complications of COVID-19 vaccines such as myocarditis, general population have become more hesitant and uncertain regarding the safety and efficacy of these mRNA vaccines. We plan to review the current literature and provide insights into their pathophysiological mechanisms for myocarditis and offer recommendations for further research studies in this regard. This will hopefully dispel some doubts and encourage more people to be vaccinated for preventing the risk of COVID-19 induced myocarditis and other associated cardiovascular complications.

Protease-activated receptors in kidney diseases: A comprehensive review of pathological roles, therapeutic outcomes and challenges.

Studies have demonstrated that protease-activated receptors (PARs) with four subtypes (PAR1-4) are mainly expressed in the renal epithelial, endothelial, and podocyte cells. Some endogenous and urinary proteases, namely thrombin, trypsin, urokinase, and kallikrein released during diseased conditions, are responsible for activating different subtypes of PARs. Each PAR receptor subtype is involved in kidney disease of distinct aetiology. PAR1 and PAR2 have shown differential therapeutic outcomes in rodent models of type-1 and type-2 diabetic kidney diseases due to the distinct etiological basis of each disease type, however such findings need to be confirmed in other diabetic renal injury models. PAR1 and PAR2 blockers have been observed to abolish drug-induced nephrotoxicity in rodents by suppressing tubular inflammation and fibrosis and preventing mitochondrial dysfunction. Notably, PAR2 inhibition improved autophagy and prevented fibrosis, inflammation, and remodeling in the urethral obstruction model. Only the PAR1/4 subtypes have emerged as a therapeutic target for treating experimentally induced nephrotic syndrome, where their respective antibodies attenuated the podocyte apoptosis induced upon thrombin activation. Strikingly PAR2 and PAR4 subtypes involvement has been tested in sepsis-induced acute kidney injury (AKI) and renal ischemia-reperfusion injury models. Thus, more studies are required to delineate the role of other subtypes in the sepsis-AKI model. Evidence suggests that PARs regulate oxidative, inflammatory stress, immune cell activation, fibrosis, autophagic flux, and apoptosis during kidney diseases.

Wnt/ß-catenin antagonist pyrvinium rescues high dose isoproterenol induced cardiotoxicity in rats: Biochemical and immunohistological evidences.

The up-regulation of Wnt/ß-catenin pathway induces cardiac function abnormalities, hypertrophy, and fibrosis in diabetic hypertensive and pressure overload models. The present study investigates the cardioprotective effects of Wnt/ß-catenin inhibition on isoproterenol (ISO) induced cardiotoxicity in rats. ISO was administered at a dose of 85 mg/kg (s.c) for 2 days. Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg, p.o) was given 2h prior and glibenclamide at a dose of 5 mg/kg; p.o, 2 h after ISO injection. Cardiac function parameters were assessed on isolated hearts by using automated Biopac apparatus. The ß-catenin transcription and expression was detected by RT-PCR technique and immunohistochemical method. Serum and cardiac tissue biochemical changes including cardiac troponin-I, CK-MB, LDH, anti-oxidant enzyme levels, inflammatory cytokines, and membrane associated Na+/K + ATPase and Ca2+ATPase and caspase-3 activity, collagen content, fibronectin protein levels were evaluated in various study groups. Histological studies were also carried out to analyze the cardiomyocyte damage, hypertrophy, fibrosis, and necrosis, while α-SMA, TGF-ß expression was checked by immunostaining. ISO administration enhanced ß-catenin gene expression and transcription which promoted oxidative and nitrosative stress, inflammatory cytokine release, reduced ATP levels, induced over-expression of fibrotic proteins resulting in cardiac hypertrophy, myocardial necrosis, functional and histological changes. However, antagonism of Wnt/ß-catenin pathway attenuated these ISO induced pathological manifestations. Notably, the co-treatment with ATP-sensitive K+ channel inhibitor partially, reduced the cardioprotective effects of Wnt/ß-catenin blocker pyrvinium in ISO rats. Thus Wnt/ß-catenin inhibition exhibits cardioprotective in ISO model by anti-oxidant, anti-inflammatory, anti-fibrotic properties and by possible involvement of ATP-sensitive potassium channel activation.

Is Regular Probiotic Practice Safe for Management of Sepsis?

For decades, the gut has been thought to play an important role in sepsis pathogenesis. Sepsis is a serious life-threatening, chronic condition of an infection caused by dysregulated host immune response in most of the intensive care unit patients. Probiotics have dual roles in polymicrobial sepsis i.e. probiotics may induce sepsis in many cases and may prevent its prognosis in many cases. Experimental evidence from both pre-clinical and clinical studies have demonstrated that probiotic therapy ameliorates various inflammatory mediators such as tumor necrosis factor, interleukin-10 (IL-10), IL-6, etc., in septicemia. In addition, probiotic use was also found to reduce the severity of pathological conditions associated with irritable bowel disorder and prevent development of endocarditis in septicemia. On contrary, probiotic therapy in neonatal and athymic adult mice fail to provide any beneficial effects on mortality and sepsis-induced inflammation. Importantly, in few clinical trials probiotic use was found to aggravate sepsis by promoting inflammatory cascade rather than suppressing it. This review discusses various studies regarding the beneficial or harmful effects associated with probiotic therapy in sepsis.

Roflumilast improves resolution of sepsis-induced acute kidney injury by retarding late phase renal interstitial immune cells infiltration and leakage in urinary sediments.

Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S-AKI) and tests the pharmacological effects of PDE-4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative-inflammatory stress biomarkers were assessed after 24 h. PDE-4 inhibitor was administered for 7 days prior to induction of S-AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase-4B, 4D isoforms, enhanced vascular permeability, caspase-3 and myeloperoxidase activity, electrolyte imbalance, reduced Na+ K+ ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre-treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper-inflammation and leukocyte infiltration was detected in late phase of S-AKI. Roflumilast pre-treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti-inflammatory effects mediated by up-regulation of renal cAMP levels.

Trimetazidine an emerging paradigm in renal therapeutics: Preclinical and clinical insights.

Trimetazidine (TMZ) is a well-known anti-ischemic agent used for the treatment of angina pectoris. In the past decades, the efficacy of this drug has been tested in a wide range of kidney injuries, including drug-induced nephrotoxicity (DIN), radio-contrast agent-induced nephropathy, and surgically induced renal ischemic injury. TMZhas renoprotective effects by attenuating oxidative stress, inflammatory cytokine release, maintaining oxygen and energy balance. Moreover, TMZ administration prevented kidney graft rejection in the porcine model by suppressing the infiltration of mononuclear cells, preserving mitochondrial functions, and maintaining Ca+ homeostasis. In DIN and diabetic kidney diseases,TMZ treatment prevents renal injury by inactivating immune cells, attenuating renal fibrosis, inflammation, apoptosis, and histological abnormalities. Interestingly, the clinical therapeutic efficacy of TMZ has also been documented in pre-existing kidney disease patients undergoing contrast exposure for diagnostic intervention. However, the mechanistic insights into the TMZ mediated renoprotective effects in other forms of renal injuries, including type-2 diabetes, drug-induced nephrotoxicity, and hypertension-induced chronic kidney diseases, remain uninvestigated and incomplete. Moreover, the clinical utility of TMZ as a renoprotective agent in radio-contrast-induced nephrotoxicity needs to be tested in a large patient population. Nevertheless, the available pieces of evidence suggest that TMZ is a promising and emerging renal therapy for the treatment and management of kidney diseases of variable etiologies. This review discusses the various pre-clinical and clinical findings and provides mechanistic insights into the TMZ mediated beneficial effects in various kidney diseases.

Wnt/ß-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction.

Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/ß-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/ß-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac ß-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (dp/dt max.) and minimum developed pressure (dp/dt min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat's heart. Also, septic rat's heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/ß-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.

"Adenosine an old player with new possibilities in kidney diseases": Preclinical evidences and clinical perspectives.

Renal injury might originate from multiple factors like ischemia reperfusion (I/R), drug toxicity, cystic fibrosis, radio contrast agent etc. The four adenosine receptor subtypes have been identified and found to show diverse physiological and pathological roles in kidney diseases. The activation of A1 adenosine receptor (A1) protects against acute kidney injury by improving renal hemodynamic alterations, decreasing tubular necrosis and its inhibition might facilitate removal of toxin or drug metabolite in chronic kidney disease models. Furthermore, recent findings revealed that A2A receptor subtype activation regulates macrophage phenotype in experimental models of nephritis. Interestingly the emerging role of adenosine kinase inhibitors in kidney diseases has been discussed which act by increasing adenosine availability at target sites and thereby promote A2A receptor stimulation. In addition, the least explored adenosine receptor subtype A3 inhibition was observed to exert anti- oxidant, immunosuppressive and anti-fibrotic effects, but more studies are required to confirm its benefits in other renal injury models. The clinical studies targeting A1 receptor in patients with pre-existing kidney disease have yielded disappointing results, perhaps owing to the origin of unexpected neurological complications during the course of trial. Importantly, conducting well designed clinical trials and testing adenosine modulators with lesser brain penetrability could clear the way for clinical approval of these agents for patients with renal functional impairments.

Effects of single and dual RAAS blockade therapy on progressive kidney disease transition to CKD in rats.

Ischemic reperfusion (I/R) is the primary cause of acute kidney injury (AKI) in hospitalized patients. Although AKI resolution occurs in few days, it predisposes kidneys to progressive renal injury. Previously, administration of rennin-angiotensin-aldosterone system (RAAS) blocker spironolactone in acute phase was reported to attenuate various manifestations of chronic kidney disease (CKD) in rats. The present study investigates the effects of RAAS blockade during progressive kidney disease (30 days onwards) on CKD outcomes in rodent model of I/R injury. CKD was induced by clamping both renal pedicles for 45 min followed by 90 days of reperfusion in rats. Single and dual RAAS blocker therapy was initiated at 30 days post-I/R injury and continued until the end of the study period. Evaluation of proteinuria and creatinine levels was done every 30 days in various study groups. Assessment of CKD was done by analyzing renal tissue oxidative stress, inflammatory biomarker levels, and histological changes after 90 days of I/R injury. After 90 days, I/R rat kidneys displayed hypertrophy, reduced body weight, increased oxidative stress, elevated inflammatory biomarker levels, and histological abnormalities such as glomerulosclerosis, mesangial expansion, and tubulointerstitial fibrosis. Treatment with losartan or spironolactone alone significantly reduced various CKD-associated features. Remarkably, combined treatment with dual RAAS blocker in low dose or high dose exhibited highest beneficial effects on various parameters in CKD model, with low-dose combination showing fewer side effects. Therefore, we propose that combined low-dose RAAS blockade therapy might serve as a better therapeutic approach for retarding progressive kidney disease transition to CKD.

Ageing reduces angiotensin II type 1 receptor antagonism mediated pre-conditioning effects in ischemic kidneys by inducing oxidative and inflammatory stress.

BACKGROUND: Ischemia/reperfusion (I/R) injury is a common cause of acute kidney injury (AKI), which occurs clinically during renal organ transplantation and major cardiac surgeries. Previously, it was demonstrated that angiotensin II type 1 receptor (AT1) receptor antagonism is beneficial in the resolution of AKI episodes in young rats by reducing inflammation and oxidative stress. However, studies have shown that aged kidneys are refractory to surgical ischemic pre-conditioning due to increased oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. Therefore, the present study was designed to evaluate the effects of pharmacologically induced pre-conditioning on I/R induced AKI in aged kidneys. METHODS: AKI was induced by clamping both renal pedicels for 45 min followed by 24 h of reperfusion. The AT1 receptor antagonist, losartan was administered for three days prior to I/R injury induction in both aged and young rats. Renal outcomes were assessed by serum creatinine, creatinine clearance and proteinuria, renal antioxidant enzyme assays, membrane Na+K+ATPase activity, inflammatory biomarkers, and histological studies. RESULTS: AKI developed 24 h post ischemia, as indicated by elevated serum creatinine levels, proteinuria, oxidative stress, reduced membrane Na+K+ATPase activity, increased inflammatory biomarkers levels and histological damage including cellular infiltration, tubular thickening, tubular dilation and necrosis. Losartan pre-treatment significantly improved renal dysfunction and histological alterations in young rats subjected to I/R injury. However, this treatment did not prevent various AKI manifestations in aged rats due to elevated oxidative and inflammatory stress mediated via tubular dysfunction and damage. CONCLUSION: We conclude that AT1 receptor antagonism is not beneficial against renal I/R induced AKI in aged rats.

Dietary restriction regimens for fighting kidney disease: Insights from rodent studies.

This review critically discusses the research findings on the effects of various dietary restriction regimens in rodent models of kidney disease. Long-term caloric restriction executed at both early and progressive stages of kidney disease was found to exert beneficial effects in rodents. Moreover, some studies have also demonstrated the efficacy of short-term caloric restriction in treating the kidney disease of variable aetiologies possibly by improving mitochondrial dysfunction, autophagy process and suppression of inflammation. However, the mechanisms underlying these short-term caloric restriction mediated protective effects in rodent models of kidney disease are not completely understood. Importantly, few available evidences have also suggested that carbohydrate restriction can exert beneficial effects in aging and experimentally induced renal injury models, but the mechanisms are not explored yet. Interestingly, the benefits of low protein diet in kidney disease models are extensively reported in literature. However, in most of these studies implementation of the low protein dietary regimen was found to associated with increased high carbohydrate and caloric intake (non-isocaloric). Thus, testing the effects of low protein diet under isocaloric conditions might further help to particularly understand the role of dietary protein content in pathology of kidney disease. Moreover, the direct evidences comparing the efficacy of various dietary restriction regimens in rodent models of kidney diseases are also scarce at present.