Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although renal disease is the most prominent feature of the lysosomal storage disease cystinosis, corneal cystine crystal formation remains a major complication, leading to photophobia, corneal erosions, and keratopathies. Moreover, the extent of corneal crystal accumulation reflects the course and severity of the disease itself, and the cornea is accessible to direct examination. Therefore, we employed a scoring system, based on a library of slit-lamp photographs of corneas with increasing crystal densities (0.00-3.00), to assess the degree of crystal accumulation in 170 patients with nephropathic cystinosis examined at the National Institutes of Health between 1976 and 2000. None of the patients had received topical cystine-depleting therapy at the time of the evaluation. In this natural history study, infants in the first year of life had absent or minimal corneal crystals, i.e., a corneal cystine crystal score (CCCS) of 0 or 0.25. However, the CCCS increased linearly with age, such that every patient had visible crystals by 16 months of age, and plateaued at approximately 3.00 by early adolescence. Longitudinal studies in representative patients support the cross-sectional results. Individuals homozygous for the common 57-kb deletion involving the cystinosis gene (CTNS) displayed the same course of corneal crystal accumulation as did individuals not bearing the large deletion. Patients with ocular or nonnephropathic cystinosis had CCCSs that were, in general, half those expected for patients with nephropathic cystinosis of the same age. Administration of 0.55% cysteamine eyedrops, given 6 to 12 times per day, dissolved corneal cystine crystals in 10 representative patients with nephropathic cystinosis aged 1 to 32 years within 8 to 41 months.
Mol Genet Metab
PMID:Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. 1100 3

Hepatocyte growth factor (HGF) is an injury-released growth factor with diverse effects on epithelial and endothelial cells. These effects include proliferation, migration, extracellular matrix production and tubulogenesis. These activities allow HGF to function as an organizer of repair processes that bring about restoration of tubular function following renal injury. However, while HGF has been demonstrated to accelerate recovery of renal function after an acute insult, prolonged exposure to elevated levels of HGF can reduce renal function and may contribute to progressive renal disease. This review will describe the cellular activities of HGF, how they pertain to renal repair and the therapeutic application of regulating HGF activity in acute versus chronic renal disease.
Cell Mol Life Sci 1999 Oct 30
PMID:Hepatocyte growth factor in renal disease: cause or cure? 1121 91

Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor kappaB (NF-kappaB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L-N(6)-(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-kappaB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by (1) increased renal cortical malondialdehyde; (2) reduced creatinine clearance; and (3) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-kappaB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.
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PMID:Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats. 1146 42

The initial description of murine strains deficient in complement component C5 has been followed by the recognition in a range of animal species of a variety of natural complement component deficiencies, many of which have been characterized at the molecular level. The use of such species in inflammatory and infectious experimental models has led to significant progress in understanding the role of specific complement factors (and pathways) in disease pathogenesis. Deficiencies of early complement factors are characterized by impairment of immune response, possibly due to defective processing of immune complexes. Complete (but not partial) deficiency of the central component C3 predisposes affected animals to significant risk of infection and renal disease. Studies in species deficient in the terminal pathway component C6 are particularly relevant for investigating the pathogenetic role of the terminal membrane attack complex (MAC), implicating it as a causative agent in diverse inflammatory insults such as reperfusion injury, glomerular damage, and xenograft hyperacute rejection. Further investigations in such naturally deficient strains, added to results derived from studies in knockout animals, are likely to expand our understanding of the role of the activated complement system in experimental inflammatory disease, with significant potential implications for the treatment of human disease.
Mol Biotechnol 2001 Jun
PMID:Animal models of inherited complement deficiency. 1147 55

Congenital nephrotic syndrome of the Finnish type (CNF or NPHS1) is an autosomal recessive kidney disorder resulting in severe proteinurea and renal dysfunction. Although the disease occurs predominantly in the Finnish population, many cases in other populations have also been reported. The disease gene (NPHS1) encodes nephrin, a podocyte transmembrane protein that is an essential component of the podocyte slit diaphragm, the renal ultrafilter. Since the discovery of the gene, many mutations have been reported in the NPHS1 gene in patients with diverse ethnic background. A surprisingly large number of these mutations are missense mutations resulting in single amino acid substitutions. In order to study the pathomechanism of these missense mutations, we have investigated the fate of 21 such mutations hitherto identified in NPHS1 patients. Immunostaining of stable transfected cells expressing the nephrin mutants demonstrated that most of the mutants showed only endoplasmic reticulum (ER) staining and no detectable cell surface localization. Immunoelectron microscopy of cells expressing the wild-type and a mutant nephrin further confirmed that the mutant nephrin could be abundantly found in the ER but not on the plasma membrane. Subcellular fractionation of wild-type and a mutant cell line clearly showed an altered subcellular distribution and molecular mobility of the mutant nephrin. In summary, our data indicate that a defective intracellular nephrin transport, most likely due to misfolding, is the most common consequence of missense mutations in NPHS1.
Hum Mol Genet 2001 Nov 01
PMID:Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. 1172 50

A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of nitric oxide (NO). Thus, ENOS, the gene coding for the endothelial nitric oxide synthase (eNOS), could have a modifier effect in ADPKD. In order to test this hypothesis, we genotyped 173 unrelated ADPKD patients from Belgium and the north of France for the Glu298Asp, intron 4 VNTR and T-786C polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In males (n = 93), the Glu298Asp polymorphism was associated with a lower age at ESRD (Glu/Asp + Asp/Asp: 49.0 +/- 1.2 years, n = 53; Glu/Glu: 53.5 +/- 1.5 years, n = 40; simple regression, P = 0.02; multiple regression, P = 0.006). This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NO synthase (NOS) activity was decreased in renal artery samples from ADPKD males harbouring the Asp298 allele, in association with post-translational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. In conclusion, the frequent Glu298Asp polymorphism of ENOS is associated with a 5 year lower mean age at ESRD in this subset of ADPKD males. This effect could be due to a decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO.
Hum Mol Genet 2002 Feb 01
PMID:Modifier effect of ENOS in autosomal dominant polycystic kidney disease. 1182 42

Autosomal dominant medullary cystic kidney disease (ADMCKD) is an adult-onset heterogeneous genetic nephropathy characterized by salt wasting and end-stage renal failure. The gene responsible for ADMCKD-1 was mapped on chromosome 1q21 and it is flanked proximally by marker D1S498 and distally by D1S2125, encompassing a region of approximately 8 cm. Within this region there are a large number of transcribed genes including NPR1 that encodes the atrial natriuretic peptide receptor 1. This receptor plays a crucial role in regulation of blood pressure by facilitating salt excretion. Based on its function we hypothesized this gene as a reasonable candidate for the MCKD1 locus. DNA mutation screening was performed on the entire NPR1 gene-coding sequence and some of the 5' prime-UTR and 3'-UTR sequences. The samples investigated belonged to patients of five large ADMCKD-1 Cypriot families. The screening revealed two novel polymorphisms, one intragenic at amino acid position 939, which was occupied by either arginine or glutamine, and a second one located in the 3' prime-UTR, 29 nucleotides downstream of the NPR1 stop codon. The latter was a single nucleotide C insertion/deletion in a stretch of three or four Cs. No relationship was present between any allele of the two polymorphisms and the disease, as both alleles were observed in both affected and healthy subjects. In addition, no association was observed between the disease and another rare 8-bp deletion polymorphism at the 5' prime-UTR of NPR1 and the disease. Based on these findings it is unlikely that NPR1 is the same as the MCKD1 gene, although it is presently unknown whether it plays a disease modifying role.
Mol Cell Probes 2001 Dec
PMID:Novel NPR1 polymorphic variants and its exclusion as a candidate gene for medullary cystic kidney disease (ADMCKD) type 1. 1185 79

The advanced stage of the glycation process (also called the "Maillard reaction") that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients and in the aging process. AGEs elicit a wide range of cell-mediated responses that might contribute to diabetic complications, vascular disease, renal disease, and Alzheimer's disease. Recently, it has been proposed that AGE are not only created from glucose per se, but also from dicarbonyl compounds derived from glycation, sugar autoxidation, and sugar metabolism. However, this advanced stage of glycation is still only partially characterized and the structures of the different AGEs that are generated in vivo have not been completely determined. Because of their heterogeneity and the complexity of the chemical reactions involved, only some AGEs have been characterized in vivo, including N-carboxymethyllysine (CML), pentosidine, pyrraline, and crosslines. In this article, we provide a brief overview of the pathways of AGE formation and of the immunochemical methods for detection of AGEs, and we also provide direct immunological evidence for the existence of five distinct AGE classes (designated as AGE-1 to -5) within the AGE-modified proteins and peptides in the serum of diabetic patients on hemodialysis. We also propose pathways for the in vivo formation of various AGEs by glycation, sugar autoxidation, and sugar metabolism.
Curr Mol Med 2001 Jul
PMID:Alternative routes for the formation of immunochemically distinct advanced glycation end-products in vivo. 1189 79

Complications of diabetes have a genetic influence. Since increased inducible nitric oxide synthase (iNOS) gene ( NOS2A) expression can contribute to tissue damage, NOS2A is a worthy candidate for such a role. We therefore tested a 4-bp insertion/deletion (+/-) polymorphism 0.7 kb upstream of NOS2A for association with complications in type 2 diabetes patients, and also performed transient transfection experiments to examine the effect of this variant on promoter activity in kidney cells in culture. We investigated 379 Caucasian type 2 diabetes patients of British/European descent, 93 of whom had microalbuminuria, 26 overt nephropathy, 46 retinopathy, and 73 clinical neuropathy. Genotyping for the variant was carried out by PCR and automated Genescan analysis. Transient transfection studies involved the renal HEK 293 cell line and luciferase reporter gene constructs containing 1.1 kb of 5'-flanking DNA from '+' or '-' allele homozygotes. We found that the '+' allele frequency in patients without microalbuminuria was 12%, but was 23% in those with microalbuminuria ( P=0.0005), and was 26% in those with nephropathy ( P=0.0007), 22% in those with retinopathy ( P=0.037), and 23% in those with neuropathy ( P=0.045). The odds ratios for homozygote +/+ to have microalbuminuria or nephropathy were 2.4 (95% CI 1.4-4.2, P=0.0023) and 5.4 (95% CI 1.8-16, P=0.0009), respectively. Luciferase reporter gene constructs containing 1 kb of NOS2A promoter DNA for each allele were made and sequence analysis confirmed that the +/- variation was the only sequence difference present. Transient transfection of these into HEK 293 cells revealed 25 times higher reporter gene activity for the '+' allele compared with the '-' allele. Gel shift analysis with 30mer oligonucleotides corresponding to each allele showed specific binding to nuclear extracts, being greater for the '+' allele. Thus the '+' allele of the NOS2A promoter variant may confer higher iNOS expression, and could contribute to complications of type 2 diabetes, especially in the approximately 5% of patients homozygous for this variant.
J Mol Med (Berl) 2002 Feb
PMID:Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes. 1190 46

Low-molecular advanced glycation end-products (AGEs)-degradation products resulting from a proteolysis of tissue or circulating AGEs represent up to 80% of AGE plasma immunoreactivity. These AGE peptides contribute to the dramatic increase in AGE levels in end-stage renal disease even in the absence of diabetes. Because glomerular filtered AGE-degradation products may accumulate within intracellular compartments of proximal tubular epithelial cells, we investigated whether there is a pathway potentially mediating damaging effects of AGE-degradation products by perturbation of the function of the tubuloepithelium. Proximal tubular-derived rat kidney cells (IRPTC) were incubated with high-molecular AGEs highly modified by incubation of bovine serum albumin (BSA) with glucose for 50 days in vitro, and with low-molecular AGE-degradation products derived from proteolytic cleavage and isolated in the molecular range between 1 and 30 kDa. The proliferation of IRPTC (3H-thymidine incorporation) was reduced to 89+/-1% and 69+/-2% after 24 hr of incubation with BSA-AGE and BSA-AGE-degradation products, respectively. The cell viability of IRPTC was reduced significantly to 59+/-15% and 31+/-13% after 144 hr of incubation with BSA-AGE and BSA-AGE-degradation products, respectively. Conditioned media obtained from IRPTC incubated for 72 hr with BSA-AGE and its degradation products increased the proliferation rate of renal fibroblasts (RFb) to 222+/-24% and 449+/-40%, respectively. Incubation of IRPTC with BSA-AGE-degradation products increased the expression of endothelin-1 (ET-1) mRNA to 210% after 1 hr; the expression of platelet-derived growth factor-B (PDGF-B) mRNA reached 184% after 2 hr. Regarding the toxicity of AGEs to the kidney, low-molecular weight AGE-degradation products possibly form an individual fraction with a comparatively higher toxic potential.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:In vitro-prepared advanced glycation end-products and the modulating potential of their low-molecular weight degradation products in IRPTC-A rat proximal-tubular derived kidney epithelial cell line. 1193 67


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