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.

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.

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.