Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used cloning in silico coupled with polymerase chain reaction to demonstrate that IHG-2 is part of the 3'-untranslated region of gremlin, a member of the DAN family of secreted proteins that antagonize the bioactivities of members of the transforming growth factor (TGF)-beta superfamily. Mesangial cell gremlin mRNA levels were induced by high glucose, cyclic mechanical strain, and TGF-beta1 in vitro, and gremlin mRNA levels were elevated in the renal cortex of rats with streptozotocin-induced diabetic nephropathy in vivo. gremlin expression was observed in parallel with induction of bone morphogenetic protein-2 (BMP-2), a target for gremlin in models of cell differentiation. Together these data indicate that (a) IHG-2 is gremlin, (b) gremlin is expressed in diabetic nephropathy in vivo, (c) both glycemic and mechanical strain stimulate mesangial cell gremlin expression in vitro, (d) high glucose induces gremlin, in part, through TGFbeta-mediated pathways, and (e) Gremlin is a potential endogenous antagonist of BMPs within a diabetic glomerular milieu.
 ...
PMID:IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1. 1074 62

The past two decades have yielded major advances in our understanding of the pathogenetic mechanisms that cause diabetic nephropathy. Of particular interest is the emerging paradigm of the recapitulation of developmental programmes within the diabetic kidney. Recently we have used the complementary techniques of suppression subtractive hybridization and Affymetrix GeneChips to assess changes in gene expression in human mesangial cells subjected to high ambient glucose concentrations and cyclic mechanical strain in vitro, the latter being models of hyperglycaemia and glomerular hypertension, respectively. In this review, we will focus on the potential role of one such differentially expressed gene, namely gremlin, in the pathogenesis of diabetic nephropathy. In the context of developmental nephrology, gremlin warrants special mention. Gremlin is a 184 amino acid protein and a member of the cysteine knot superfamily. The protein is highly conserved during evolution and is present in soluble and cell-associated forms. It belongs to a novel family of bone morphogenetic protein (BMP) antagonists that includes the head-inducing factor Cerberus and the tumour suppressor DAN. These proteins play important roles in limb development and neural crest cell differentiation. Evidence will be presented that mesangial cell gremlin expression is up-regulated by high ambient glucose, cyclic mechanical strain and transforming growth factor-beta (TGF-beta) and that gremlin may be an important modulator of mesangial cell proliferation and epithelial-mesenchymal transdifferentiation in a diabetic milieu.
 ...
PMID:Gremlin: an example of the re-emergence of developmental programmes in diabetic nephropathy. 1238 93

One hundred and twenty-nine (87%) out of a county population of 150 eligible children with type 1 diabetes mellitus (DM) and 144 age- and sex-matched control children participated in a longitudinal, epidemiological study of the evolution of diabetic microvascular disease. The mean (SD) age of the children with DM was 12.4 (+/- 3.4) years with a mean DM duration of 4.5 (+/- 3.2) years and a mean HbA1c of 11.1 (+/- 2.2)%. Two sets of measurements were made over a period of 18 months. Pupillary adaptation in darkness (PD), as an index of sympathetic dysfunction, was assessed using a portable Polaroid pupillometer. Urinary albumin excretion, as an index of incipient nephropathy, was assessed in children with DM from a fraction of all voidings during two separate 48-h periods and was expressed as urinary albumin/creatinine ratio (A/C). Heart rate variation (HRV), as an index of cardiovascular autonomic dysfunction, was assessed using a heart rate monitor and computer. Blood pressure (BP) was measured using a random zero sphygmomanometer. Reduced PD was found in 14/129 (13.8%) children with DM and in 5.8% of the controls. The diabetic children with reduced PD had longer DM duration, higher HbA1c, raised diastolic BP and higher urinary A/C than those with normal PD. Fifty percent of these children also had increased A/C and impaired HRV, in addition to impaired PD. Another group of 25/129 (19.4%) children with DM presented intermittently raised mean urinary A/C, while five children presented persistently raised A/C in both 48-h urine collections. The characteristics which differentiated the microalbuminuric group from the normoalbuminuric one were older age, longer DM duration, poorer glycemic control, reduced PD, impaired HRV and raised diastolic BP. It seems that diabetic nephropathy (DN) and autonomic neuropathy (DAN) exist in concert in childhood DM. Diabetic children with impaired indices of DN and DAN are older, pubertal and have longer DM duration and higher HbA1c values than the rest of the diabetic population.
 ...
PMID:Coexistence of impaired indices of autonomic neuropathy and diabetic nephropathy in a cohort of children with type 1 diabetes mellitus. 1258 44

Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during diabetic nephropathy (DN) has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. In the present study, we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK (human embryonic kidney)-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readouts, Grem1 consistently demonstrated a higher affinity for BMP-2>BMP-4>BMP-7. Cell-associated Grem1 did not inhibit BMP-2- or BMP-4-mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.
...
PMID:Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7. 2537 54