Light-chain glomerulopathy with amyloid-like deposits

A 40-year-old man with rapidly progressive renal failure was found to have a lobular glomerulonephritis by renal biopsy. Immunofluorescent microscopy showed prominent glomerular deposition of both kappa and lambda light chains but no significant heavy-chain component. Ultrastructurally, electron-dense deposits in the mesangium and capillary basement membranes had a fibrillar appearance indistinguishable from amyloid. This case illustrates a "light-chain glomerulopathy" distinct from previously reported glomerulopathies associated with the deposition of light chains of a single subclass.     

[Sar, Ala] angiotensin II in cerebrospinal fluid blocks the binding of blood-borne [I]angiotensin II to the circumventricular organs

There is a specific, high affinity uptake of angiotensin II in the circumventricular organs when the peptide is injected systemically.¹¹ The question of whether angiotensin II in cerebrospinal fluid can reach angiotensin receptors in the circumventricular organs was investigated in rats by determining the effect of intraventricular administration of the angiotensin II receptor blocking peptide [Sar¹, Ala⁸]angiotensin II (saralasin) on the binding of blood-borne [¹²⁵I]angiotensin II. Other rats received intraventricular saline, intraventricular ACTH^4–10 as a peptide control, or intravenous saralasin. The brains of the rats were then sectioned and subjected to radioautography. ACTH^4–10 had no effect on angiotensin II uptake. Intraventricular saralasin reduced the uptake of blood-borne angiotensin II in the median eminence and organum vasculosum of the lamina terminalis to the same degree as intravenous saralasin, and reduced uptake in the subfornical organ and area postrema to a lesser extent. Uptake was reduced 40% in the anterior lobe of the pituitary by intraventricular saralasin and 73% by intravenous saralasin, indicating that some saralasin entered the portal vessels. Uptake in the posterior lobe was unaffected by intraventricular saralasin, but reduced by intravenous saralasin.

The data indicate that saralasin, and so presumably angiotensin II, in the cerebrospinal fluid can reach angiotensin II receptors in the circumventricular organs which bind blood-borne angiotensin II. Consequently, the effects of intraventricular angiotensin II that are also produced by intravenous angiotensin II can probably be explained by the peptide acting on the circumventricular organs.     

High-Fat Diet–Induced Adipose Tissue and Liver Inflammation and Steatosis in Mice Are Reduced by Inhibiting Sialidases

High-fat diet (HFD)–induced inflammation and steatosis of adipose tissue and liver are associated with a variety of serious health risks. Sialic acids are found as the distal terminal sugar on glycoproteins, which are removed by sialidases (neuraminidases). In humans and mice, pulmonary fibrosis is associated with up-regulation of sialidases, and injections of sialidase inhibitors attenuate bleomycin-induced pulmonary fibrosis. Sialidase levels are altered in obese rodents and humans. This report shows that for mice on an HFD, injections of the sialidase inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid inhibit weight gain, reduce steatosis, and decrease adipose tissue and liver inflammation. Compared with control, mice lacking the sialidase neuraminidase 3 have reduced HFD-induced adipose tissue and liver inflammation. These data suggest that sialidases promote adipose and liver inflammation in response to a high-fat diet.

In the United States, approximately 40% of adults are obese (body mass index, ≥30 kg/m²), leading to an estimated annual medical cost of $150 billion and approximately 200,000 deaths.1, 2, 3 Obesity is one of the most prominent risk factors for many chronic diseases, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Approximately 25% of adults in highly industrialized nations have nonalcoholic fatty liver disease, with approximately 5% of them having nonalcoholic fatty liver disease with liver inflammation (hepatitis), a more serious condition called nonalcoholic steatohepatitis.4, 5, 6 Up to 40% of individuals with nonalcoholic steatohepatitis progress to advanced liver fibrosis and eventually cirrhosis.⁷Obesity is the accumulation of body fat as the result of excessive food intake and/or lack of exercise. Obesity induces adipocyte metabolic dysregulation and the production of inflammatory cytokines, leading to systemic metabolic dysregulation, such as the inability to effectively control systemic glucose levels (insulin resistance), elevated lipid levels (dyslipidemia), and immune cell recruitment to, and activation in, adipose tissue and liver (inflammation).⁸ Excess calories lead to elevated circulating levels of glucose and free fatty acids, which force adipocytes to accumulate more lipid and expand in size, leading to increased oxidative stress in adipocytes and local hypoxia of the tissue, due to the inability of oxygen to diffuse across the tissue.^8,9 These processes lead to adipocyte cell death, initiating the activation of adipose tissue macrophages.^9,10 In the liver, excess calories lead to Kupffer cell (hepatic macrophage) activation, which promotes inflammation and increased hepatocyte fatty acid synthesis, leading to hepatic steatosis (abnormal retention of lipids within the hepatocytes) and eventual fibrosis or cirrhosis.^8,11Sialic acids are often found as the distal terminal sugar on the oligosaccharide chains of glycoconjugates, such as glycoproteins. Sialidases (alias neuraminidases) are enzymes that remove this sialic acid from glycoconjugates.¹² Neuraminidase (NEU) 1 to 4 are the four sialidases seen in mammals.¹³ N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (DANA) inhibits mammalian sialidases.¹⁴ Previous studies have found that injections of DANA or lack of NEU3 both attenuate bleomycin-induced lung fibrosis in mice.^15,16 The role of sialidases in the regulation of high-fat diet–induced obesity is unclear, with up-regulation or down-regulation of different sialidase proteins in different tissues, suggesting a complex association between obesity and sialidases.17, 18, 19 Changes in sialidase levels appear to lead to the dysregulation of insulin signaling and glucose metabolism.^18,19Because excess calories lead to adipose tissue and liver inflammation, steatosis, and fibrosis, and because injections of DANA and lack of endogenous NEU3 both inhibit bleomycin-induced lung inflammation and fibrosis, this study examined whether injections of DANA and/or endogenous NEU3 could inhibit obesity-induced adipose tissue, liver inflammation, and steatosis in a mouse model.     

Enzymatically Inactive Tissue-Type Plasminogen Activator Reverses Disease Progression in the Dextran Sulfate Sodium Mouse Model of Inflammatory Bowel Disease

Enzymatically inactive tissue-type plasminogen activator (EI-tPA) does not activate fibrinolysis, but interacts with the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor–related protein-1 (LRP1) in macrophages to block innate immune system responses mediated by toll-like receptors. Herein, we examined the ability of EI-tPA to treat colitis in mice, induced by dextran sulfate sodium. In two separate studies, designed to generate colitis of differing severity, a single dose of EI-tPA administered after inflammation established significantly improved disease parameters. EI-tPA–treated mice demonstrated improved weight gain. Stools improved in character and became hemoccult negative. Abdominal tenderness decreased. Colon shortening significantly decreased in EI-tPA–treated mice, suggesting attenuation of irreversible tissue damage and remodeling. Furthermore, histopathologic evidence of disease decreased in the distal 25% of the colon in EI-tPA–treated mice. EI-tPA did not decrease the number of CD45-positive leukocytes or F4/80-positive macrophage-like cells detected in extracts of colons from dextran sulfate sodium–treated mice as assessed by flow cytometry. However, multiple colon cell types expressed the NMDA-R, suggesting the ability of diverse cells, including CD3-positive cells, CD103-positive cells, Ly6G-positive cells, and epithelial cell adhesion molecule–positive epithelial cells to respond to EI-tPA. Mesenchymal cells that line intestinal crypts and provide barrier function expressed LRP1, thereby representing another potential target for EI-tPA. These results demonstrate that the NMDA-R/LRP1 receptor system may be a target for drug development in diseases characterized by tissue damage and chronic inflammation.

The inflammatory bowel diseases (IBDs), such as Crohn disease and ulcerative colitis, are chronic, relapsing diseases of the intestines that eventually compromise tissue structure and function.¹ Disease susceptibility genes such as the pattern recognition receptor, nucleotide-binding oligomerization domain containing 2 (NOD2), have been implicated in Crohn disease.^1,2 Dysbiosis in intestinal microbiomes also has been implicated in the onset of IBD, together with lifestyle choices, such as cigarette smoking.3, 4, 5 Once IBD is established, chronic inflammation and tissue damage dominate the clinical course and are principal targets for therapeutics development.⁶ Despite the availability of numerous drugs, many patients with moderate to severe IBD fail to remain in remission and often experience damaging flares.Tissue-type plasminogen activator (tPA) is a serine protease and major activator of the fibrinolytic system.^7,8 Recombinant tPA is Food and Drug Administration-approved for treating recent-onset stroke.⁹ The structure of tPA includes multiple domains that participate in noncovalent fibrin binding, which is essential for restricting the lytic activity of tPA to fibrin while sparing fibrinogen.10, 11, 12 tPA also binds to cell surface receptors, including the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor–related protein-1 (LRP1), which function as part of a single system to regulate cell signaling and cell physiology.13, 14, 15, 16, 17 Enzymatically inactive tPA (EI-tPA), in which the enzyme active site serine is mutated to alanine, interacts with the NMDA-R/LRP1 receptor system equivalently to enzymatically active tPA to trigger signal transduction.^16,18,19In mouse macrophages, EI-tPA binding to the NMDA-R/LRP1 receptor system blocks inflammatory cytokine expression elicited by multiple toll-like receptors (TLRs), including TLR4, TLR2, and TLR9.18, 19, 20 EI-tPA also blocks the toxicity of lipopolysaccharide in vivo in mice.¹⁸ These results suggest that EI-tPA and the NMDA-R/LRP1 receptor system constitute a novel pathway for regulating innate immunity and inflammation. EI-tPA does not activate plasminogen, thus avoiding undesirable effects on hemostasis and the possible proinflammatory activity of plasmin.^21,22 Some pattern recognition receptors outside the TLR family, such as NOD1 and NOD2, are not antagonized by EI-tPA in macrophages.¹⁹ Furthermore, because the NMDA-R is expressed by numerous cell types,^17,18,23,24 EI-tPA may regulate inflammation by targeting cells in addition to macrophages. Thus, it is not clear whether EI-tPA would be effective in counteracting pathologic conditions in which diverse pattern recognition receptors function together in diverse cells to stimulate fulminant inflammation.In this study, the dextran sulfate sodium (DSS) preclinical mouse model of colitis was used to test the activity of EI-tPA. DSS causes a chemically-induced form of colitis, in which extensive inflammatory cell infiltrates develop in the mucosa and submucosa.²⁵ Mice were treated systemically with a single dose of EI-tPA after intestinal inflammation was established. EI-tPA rapidly reversed signs and symptoms of the disease and caused significant improvement in disease biomarkers. These results indicate that EI-tPA may be efficacious as a therapeutic for complex inflammatory diseases.