Synthetic apolipoprotein A-I mimetic peptide 4F protects hearts and kidneys after myocardial infarction.

Patients undergoing coronary angiography after myocardial infarction (MI) often develop cardiac and renal dysfunction. We hypothesized that the apolipoprotein A-I mimetic peptide 4F (4F) would prevent those complications. Male Wistar rats were fed a high-cholesterol diet for 8 days. The rats were then anesthetized with isoflurane and randomly divided into five groups: a control group (sham-operated rats), and four groups of rats induced to MI by left coronary artery ligation, the rats in three of those groups being injected 6 h later, with the nonionic contrast agent iopamidol, 4F, and iopamidol plus 4F, respectively. At postprocedure hour 24, we performed the following experiments/tests (n = 8 rats/group): metabolic cage studies; creatinine clearance studies; analysis of creatinine, urea, sodium, potassium, triglycerides, total cholesterol, very low-, low- and high-density lipoproteins (VLDL, LDL, and HDL); immunohistochemistry; histomorphometry; Western blot analysis; and transmission electron microscopy. In another set of experiments (n = 8 rats/group), also performed at postprocedure hour 24, we measured mean arterial pressure, heart rate, heart rate variability, echocardiographic parameters, left ventricular systolic pressure, and left ventricular end-diastolic pressure. 4F protected against MI-induced increases in total cholesterol, triglycerides, and LDL; increased HDL levels; reversed autonomic and cardiac dysfunction; decreased the myocardial ischemic area; minimized renal and cardiac apoptosis; protected mitochondria; and strengthened endothelia possibly by minimizing Toll-like receptor 4 upregulation (thus restoring endothelial nitric oxide synthase protein expression) and by upregulating vascular endothelial growth factor protein expression. 4F-treated animals showed signs of cardiac neovascularization. The nitric oxide-dependent cardioprotection and renoprotection provided by 4F could have implications for post-MI treatment.

Synergic Renoprotective Effects of Combined ASC Therapy with RAAS Blockade in Experimental Advanced CKD.

Global prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis, contributes to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation/fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical, and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.

Acute kidney injury in a mouse model of meningococcal disease.

INTRODUCTION: Meningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease. METHODS: Female BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice. RESULTS: In the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte-macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm-Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect. CONCLUSION: Our findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

Adipose-Derived Mesenchymal Stem Cells Modulate Fibrosis and Inflammation in the Peritoneal Fibrosis Model Developed in Uremic Rats.

Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting the peritoneal membrane (PM) function. Adipose tissue-derived mesenchymal stem cells (ASC) display immunomodulatory effects and may represent a strategy to block PF. The aim of this study was to analyze the effect of ASC in an experimental PF model developed in uremic rats. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and chronic kidney disease (CKD), was developed in Wistar rats. Rats were fed with a 0.75% adenine-containing diet, for 30 days, to induce CKD with uremia. PF was induced with intraperitoneal injections of chlorhexidine gluconate (CG) from day 15 to 30. 1 × 106 ASC were intravenously injected at days 15 and 21. Rats were divided into 5 groups: control, normal rats; CKD, rats receiving adenine diet; PF, rats receiving CG; CKD+PF, CKD rats with PF; CKD+PF+ASC, uremic rats with PF treated with ASC. PF was assessed by Masson trichrome staining. Inflammation- and fibrosis-associated factors were assessed by immunohistochemistry, multiplex analysis, and qPCR. When compared with the control and CKD groups, GC administration induced a striking increase in PM thickness and inflammation in the PF and CKD+PF groups. The development of PF was blocked by ASC treatment. Further, the upregulation of profibrotic factors (TGF-ß, fibronectin, and collagen) and the increased myofibroblast expression observed in the CKD+PF group were significantly ameliorated by ASC. Beyond the antifibrotic effect, ASC showed an anti-inflammatory effect avoiding leucocyte infiltration and the overexpression of inflammatory cytokines (IL-1ß, TNF-α, and IL-6) in the PM induced by GC. ASC were effective in preventing the development of PF in the experimental model of CKD+PF, probably due to their immunomodulatory properties. These results suggest that ASC may represent a potential strategy for treating long-term PD-associated fibrosis.