Glomerular Endothelial Proliferation Research Articles

Combinational Use of Antiplatelet Medication Sarpogrelate with Therapeutic Drug Rosuvastatin in Treating High-Cholesterol Diet-Induced Chronic Kidney Disease in ApoE-Deficient Mice.

A number of metabolic disorders, including hyperlipidemia, potentially cause chronic kidney disease (CKD), one of their major chronic complications and comorbidities. Rosuvastatin is one of the widely used antiatherogenic drugs among hyperlipidemic patients. Meanwhile, sarpogrelate is not only a 5-hydroxytryptamine receptor antagonist but also an antiplatelet agent, inhibiting platelet-stimulated blood coagulation and improving peripheral circulation. In this study, a combination of sarpogrelate and/or rosuvastatin was used on CKD mice induced by a high-fat diet for 8 weeks. The mice were tested for pathological changes using histological evaluation. Tremendous alterations were found, including a remarked increase in total cholesterol and low-density lipoprotein cholesterol levels, glomerular endothelial proliferation, and mesangial expansion. Also, tubular damage and extracellular matrix accumulation occurred, namely, a marked increase in the macula densa, scattered and apoptotic loss of the apical brush border with vacuolated basophilic cytoplasm and heavily stained nuclei, and expanded Bowman's space, which were at least partially ameliorated by sarpogrelate and/or rosuvastatin treatment. The analysis of expression profiles at both the RNA and protein levels, using real-time quantitative polymerase chain reaction and Western blot analysis, indicated that LDL-R/CD68/LOX-1-positive monocyte/macrophage-mediated enhanced proinflammatory activation, including the significant upregulation of tumor necrosis factor-α and interleukin-6, was actually attenuated by sarpogrelate and/or rosuvastatin treatment. The findings indicated that sarpogrelate and/or rosuvastatin treatment potentially ameliorates CKD progression in patients with the aforementioned comorbid metabolic disorders.

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice.

Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD.

MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy

Glomerular endothelial cells (GEnCs) contribute to renal injuries in IgA nephropathy (IgAN). Here we profiled microRNAs (miRNAs) in GEnCs treated with conditioned medium from human mesangial cells in vitro. Levels of miR-223 in GEnCs decreased after incubation with the medium prepared with pIgA from patients with glomerular endothelial proliferation and were also decreased in the glomerular tissues of patients with glomerular endothelial proliferation. Mesangial-derived IL-6 caused miR-223 levels to decrease. The addition of exogenous miR-223 inhibited cell proliferation, ICAM-1 expression, and monocyte adhesion. The NF-κB and STAT3 signaling pathways collaborate during the activation process. MiR-223 mimics inhibited the nuclear localization and DNA binding of p65 and STAT3 but had no effect on the expression of upstream molecules. Instead, importin α4 and α5 (multipurpose nuclear transport receptors), validated as targets of miR-223, were responsible for the nuclear transport of p65 and STAT3. Importin α4 and α5 siRNA inhibited the nuclear localization of p65 and STAT3 and prevented cell proliferation and monocyte adhesion. The level of miR-223 in circulating endothelial cells was decreased and related to the clinical and pathological parameters. Thus, miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgAN. Monitoring the level of miR-223 in circulating endothelial cells may provide a noninvasive method for evaluating the severity of IgAN.

Experimental cadmium poisoning in sheep

Pathomorphological investigations of internal organs were made in sheep given sublethal doses of cadmium. Early histological damages in kidneys were established by renal biopsy in some experimental animals. The main histological changes were characterized by granular degeneration in proximal tubules and glomerular endothelial proliferation in kidneys, granular degeneration in hepatocytes, pericapillary oedema and activation of capillary endothelium and Kupffer cells in liver, oedematous and degenerative changes in cerebrum and in the region of Purkinje cells of cerebellum, hyperplasia and proliferation of alveolar epithelium and perivascular or peribronchial mononuclear cell infiltration in lung, and degenerative changes in the medulla and zona glomerulosa of adrenal glands.

Thrombospondin peptides are potent inhibitors of mesangial and glomerular endothelial cell proliferation in vitro and in vivo

Thrombospondin 1 (TSP1), a multifunctional, matricellular glycoprotein, is expressed de novo in many inflammatory disease processes, including glomerular disease. Short peptide fragments derived from the type I properdin repeats of the TSP1 molecule mimic anti-angiogenic and/or transforming growth factor-beta (TGF-beta)-activating properties of the whole TSP1 glycoprotein. We investigated the effects of D-reverse peptides derived from the type I domain of TSP1 in experimental mesangial proliferative glomerulonephritis in the rat (anti-Thy1 model), as well as their effects on cultured mesangial and glomerular endothelial cells. Effects of TSP peptides on proliferation of mesangial or glomerular endothelial cells in culture after growth arrest or growth factor stimulation (fibroblast growth factor-2, platelet-derived growth factor-BB, 10% fetal calf serum) were measured by [3H]thymidine incorporation assay. Adhesion of rat mesangial cells (MCs) to a TSP-peptide matrix was assayed using an attachment-hexosaminidase assay. TSP peptides were intraperitoneally injected daily in rats that had received an intravenous injection of polyclonal anti-Thy1 antibody to induce mesangial proliferative glomerulonephritis. On biopsies from days 2, 5, and 8 of anti-Thy1 disease, mesangial and glomerular endothelial proliferation, matrix expansion, mesangial activation, and microaneurysm formation were assessed. Functional parameters such as blood pressure and proteinuria were also measured. An 18-amino acid peptide (type I peptide) with anti-angiogenic and TGF-beta-activating sequences decreased mesangial and glomerular endothelial cell proliferation in vitro and in vivo and reduced microaneurysm formation and proteinuria in experimental glomerulonephritis. Analogues lacking the TGF-beta-activating sequence mimicked most effects of the type I peptide. The mechanism of action of these peptides may include antagonism of fibroblast growth factor-2 and alteration of MC adhesion. The TGF-beta-activating sequence alone did not have significant effects on mesangial or glomerular endothelial cells in vitro or in experimental kidney disease in vivo. Peptides from TSP1 may be promising therapeutics in treating glomerular disease with mesangial and endothelial cell injury.

Clinicopathology of kidneys from brain-dead patients treated with vasopressin and epinephrine

Studies were made on the biochemical and pathological conditions of kidneys of 20 brain-dead patients who were maintained for 0 to 48 days after brain death by administration of vasopressin and epinephrine. Twenty specimens were obtained by percutaneous biopsy or at autopsy. The biochemical and pathological degrees were compared with those on the day of brain death (day 0). Biochemical tests on day 0 indicated that they showed the diuretic phase of prerenal failure, and then glomerular hyperemia was extensive. Renal function recovered on day 1 and remained almost normal during the 14 day period. Their urine retained high levels of sodium and osmolarity for days 0 to 14, with mild hyponatremia and hypo-osmolarity of the plasma. Tubulointerstitial nephritis gradually became extensive. There was no significant change in the degrees of mesangial widening, mesangial cell proliferation or hyalinosis. Arterial intimal proliferation was gradually extensive after day 3 and glomerular endothelial proliferation was gradually extensive after a week. Brain-dead patients have been mostly reported to develop diabetes insipidus, but our brain-dead patients did not show any manifestation of this disease. We suggest that constant natriuresis and continuing high level of urine osmolarity might have been caused by prerenal renal failure, brain death followed by neurogenic impairment, high level of serum vasopressin, or interstitial nephritis.

The localization of circulating immune complexes in experimental serum sickness. The role of vasoactive amines and hydrodynamic forces.

In serum sickness, mechanisms by which circulating immune complexes become localized in the walls of vessels and glomeruli have been studied. In affected arteries, morphologic observations showed that circulating marker particles of carbon would rapidly deposit along the luminal surface of the internal elastic lamina. This, as in previous studies, suggested an increase in vascular permeability during which large molecules were capable of being trapped by a filtering membrane in the vessel wall. In attempts to prevent the increase in vascular permeability, rabbits were treated with antagonists of histamine and serotonin. Such treatment markedly inhibited the localization of immune complexes in glomeruli, the development of proteinuria, and glomerular endothelial proliferation. Cardiovascular lesions also were largely prevented from developing. Depletion of platelets, the principal reservoir of vasoactive amines, had a similar though less pronounced effect. While the deposition of immune complexes was inhibited, allergic inflammation in general was not, since normal rabbits treated as above were found capable of developing full Arthus reactions and acute nephrotoxic nephritis. Hydrodynamic factors were noted to be important in determining the location of arterial lesions. Studies of aortas from unmodified rabbits and from those with surgically induced coarctations of the abdominal aorta revealed intimal lesions concentrated at areas of high turbulence, such as at branches, bifurcations, outflows and zones of configurational change. Lesions in these areas were also largely inhibitable by depletion of platelets or by antagonists of histamine and serotonin.