Gremlin renal overexpression has been reported in diabetic nephropathy, pauci-immune crescentic glomerulonephritis and chronic allograft nephropathy and has been implicated in the pathophysiology of ...the progression of renal damage. However, it is unknown whether urinary Gremlin can be associated with renal functional status, renal biopsy findings and outcome. To examine these associations we studied 20 patients with ANCA+ renal vasculitis and very high urinary Gremlin (354 ± 76 ug/gCr), 86 patients with other glomerular diseases and moderately elevated urinary Gremlin (83 ± 14 ug/gCr) and 11 healthy controls (urinary Gremlin 11.3 ± 2.4 ug/gCr). Urinary Gremlin was significantly correlated with renal expression of Gremlin (r = 0.64, p = 0.013) observed in cellular glomerular crescents, tubular epithelial cells and interstitial inflammatory cells. Moreover, urinary Gremlin levels were correlated with the number of glomerular crescents (r = 0.53; p < 0.001), renal CD68 positive cells (r = 0.71; p < 0.005), tubulointerstitial fibrosis (r = 0.50; p < 0.05), and serum creatinine levels (r = 0.60; p < 0.001). Interestingly, Gremlin expression was colocalized with CD68, CD163 (monocyte/macrophage markers) and CCL18 positive cells. ROC curve analysis showed that the cutoff value of urinary Gremlin in glomerular diseases as 43 ug/gCr with 72% of sensitivity and 100% of specificity AUC: 0.96 (CI 95% 0.92-0.99 (p < 0.001). For ANCA+ renal vasculitis the value of urinary Gremlin of 241 ug/gCr had 55% of sensitivity and 100% of specificity AUC: 0.81 (CI 95% 0.68-0.94) (p < 0.001. Based on these results we propose that urinary Gremlin represents a non-invasive biomarker in ANCA+ renal vasculitis, and suggest a role of Gremlin in the formation of crescents.
A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains ...an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic nephropathy (DN) is currently a leading cause of end-stage renal failure worldwide. Gremlin was identified as a gene differentially expressed in mesangial cells exposed to high glucose and ...in experimental diabetic kidneys. We have described that Gremlin is highly expressed in biopsies from patients with diabetic nephropathy, predominantly in areas of tubulointerstitial fibrosis. In streptozotocin (STZ)-induced experimental diabetes, Gremlin deletion using Grem1 heterozygous knockout mice or by gene silencing, ameliorates renal damage. To study the in vivo role of Gremlin in renal damage, we developed a diabetic model induced by STZ in transgenic (TG) mice expressing human Gremlin in proximal tubular epithelial cells. The albuminuria/creatinuria ratio, determined at week 20 after treatment, was significantly increased in diabetic mice but with no significant differences between transgenic (TG/STZ) and wild-type mice (WT/STZ). To assess the level of renal damage, kidney tissue was analyzed by light microscopy (periodic acid-Schiff and Masson staining), electron microscopy, and quantitative PCR. TG/STZ mice had significantly greater thickening of the glomerular basement membrane, increased mesangial matrix, and podocytopenia vs. WT/STZ. At the tubulointerstitial level, TG/STZ showed increased cell infiltration and mild interstitial fibrosis. In addition, we observed a decreased expression of podocin and overexpression of monocyte chemoattractant protein-1 and fibrotic-related markers, including transforming growth factor-β1, Col1a1, and α-smooth muscle actin. Together, these results show that TG mice overexpressing Gremlin in renal tubules develop greater glomerular and tubulointerstitial injury in response to diabetic-mediated damage and support the involvement of Gremlin in diabetic nephropathy.
13 adenoviruses (Ad) from the urine of 10 patients with acquired immunodeficiency syndrome (AIDS) were characterised by haemagglutination inhibition and restriction endonuclease analysis of their ...DNA. The haemagglutinin (HA) for 6 of these isolates was found to be that of Ad34/35. 3 other isolates were found to have Ad7 HA and the remaining 4 viruses were found to have both phenotypes. In contrast, the restriction patterns were more homogeneous than anticipated from the serological analysis. 11 isolates had a SmaI-restriction pattern identical to Ad35, and 2 isolates, which lacked one of the 9 Ad35 SmaI-restriction sites, were identical to Ad34. Analyses with other restriction enzymes reinforced the conclusion that the genomes of all isolates resemble that of Ad35 (and Ad34) more than they resembled the previously isolated Ad7 subtypes. The discrepancy between the restriction endonuclease and the serological analyses is best explained by assuming that some of these new isolates are recombinants between a small part (less than 10%) of the Ad7 genome coding for HA and greater than 90% of the Ad35 genome. It is therefore important to characterise both the genotype and the HA for this potentially important group of pathogens in AIDS patients.
Echinococcosis is an important disease with regard to public health and the leading role that humans have in fulfilling the transmission cycle. The objective of this study was to determine the ...copro-prevalence of Echinococcus granulosus in dogs from homes in Huancarama, Peru, and the factors associated with this infection. The research was basic, prospective, quantitative, observational, cross-sectional, and analytical. This study was approved by the Institutional Ethics Committee for the Use of Animals (CIEA) and the Institutional Research Ethics Committee (CIEI) of the Universidad Peruana Cayetano Heredia. The sample comprised of 519 homes. A geographic information system (GIS) was used to develop layers of information on the study area with georeferencing of the locations of these homes. Information processing was performed using Excel for Windows 2010, Statistical Package for the Social Sciences SPSS 25 software, and ArcGIS 10.8. Univariate and multivariate logistic regression tests were performed to determine the possible associations. Categorical variables were statistically contrasted using the chi-square test with 95% confidence intervals and P ? 0.05, which indicated the extreme degree of significance. It was found that 94.4% of the houses had dogs and that the prevalence of E. granulosus was 27.7% (95/343; 95% CI 22.8-32.6). The distance from the house to the cattle slaughterhouse was associated with disease occurrence (P < 0.01). Locations in the Suni altitude zone presented a higher prevalence (41.8%) (P < 0.05). Lack of knowledge that humans can contract echinococcosis was associated with disease occurrence (P < 0.05).
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