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

We have previously reported increased activity of Na+/H+ and Na+/Li+ exchanges in red blood cells (RBC) of patients with hypertension and diabetic nephropathy. The presence in human red blood cells (RBC) of insulin receptors has led us to examine the effects of this hormone on the kinetic parameters of Na+/H+ exchange as a first approach to define its mechanism of action. The antiporter activity was measured as net Na+ influx driven by an outward H+ gradient in acid-loaded, Na-depleted RBCs preincubated with or without (w/wo) insulin (0 to 100 microU/ml) for different time periods. The effects of insulin on the H+ and Na+ activation kinetics of Na+/H+ exchange were examined in RBCs of normal subjects fasted for 12 hours. Insulin (50 microU/ml for 1 hr) increased the Vmax from 28 +/- 6 to 49 +/- 8 mmol/liter cell x hr (N = 10, P < 0.0005) and the Km for Na+ from 72 +/- 10 to 142 +/- 19 mM (N = 4, P < 0.05) but did not change the Km for intracellular H+. Insulin also increased the Vmax of Na+/Li+ exchange at pHi 7.4 (0.34 +/- 0.03 to 0.45 +/- 0.04 mmol/liter cell x hr, N = 9, P < 0.005) as well as the Km for Na+ (31 +/- 3 to 6 +/- 10 mM, P < 0.0003). Therefore, insulin can modulate Na+ sites of Na+/Li+ or Na+/H+ exchanges independent of the occupancy of H+ sites to favor the release of bound Na+ into the cytoplasm. Insulin stimulation of Na+/H+ exchange required endogenous cytosolic Ca2+ levels. The kinetic effects of insulin on Na+/H+ and Na+/Li+ exchanges were imitated by okadaic acid (300 microM), an inhibitor of protein phosphatases which dephosphorylate serine-threonine residues. Okadaic acid increased the Vmax of Na+/H+ and Na+/Li+ exchanges and the Km for Na+ as insulin did. In conclusion, insulin stimulation of the Na+/H+ antiporter occurs by a novel kinetic mechanism leading to a decreased affinity for external Na+ without changes in the affinity for Hi. On the basis that insulin effects were imitated by okadaic acid, we hypothesize that this hormone may increase the phosphorylated state of serine-threonine residues of this antiporter protein.
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PMID:Insulin activation of red blood cell Na+/H+ exchange decreases the affinity of sodium sites. 796 48

The epidemiological evidence that only a subset of diabetic patients are susceptible to renal damage and the demonstration of clear familiar clustering of diabetic nephropathy are consistent with the possibility that genetic factors may explain the liability to or protection from renal disease of diabetic patients. A predisposition to hypertension and cardiovascular disease may be an important determinant of susceptibility to renal disease and its cardiovascular complications in diabetes since raised blood pressure [1] and an increased frequency of cardiovascular disease [2] are more prevalent in parents of diabetic patients with nephropathy. These results have raised growing interest in the search for intermediate phenotypes significantly associated with diabetic nephropathy, poorly influenced by environment, stable with age, easy to quantify and possibly dependent upon a single major gene effect. Such intermediate phenotypes can be useful for early diagnosis and would help clarify the molecular mechanisms leading to diabetic nephropathy. An elevation of Na+/H+ antiporter activity has consistently been associated with diabetic renal disease both in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients, making this cell membrane exchanger system an ideal intermediate phenotype for the study of diabetic nephropathy.
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PMID:Sodium-hydrogen antiporter: its possible role in the genesis of diabetic nephropathy. 914 Sep 84

Previous studies have shown that cultured skin fibroblasts (SFs) from insulin-dependent diabetic mellitus (IDDM) patients with diabetic nephropathy (DN) exhibit both increased proliferation and Na+/H+ antiporter activity. The present study correlated the growth rate and mRNA expression of integrin subunits, extracellular matrix molecules, and transforming growth factor-beta in cultured SFs, with the biopsy determined rate of development of DN lesions ranging from slow to rapid in nine IDDM patients. These varying rates of development of DN lesions were expressed by a mesangial expansion score as estimated by the rate of change in mesangial fraction volume per year. Cultured SF proliferation by direct cell counts positively correlated with mesangial expansion score (r = 0.65; P < 0.05). Expression of cultured SF alpha3 integrin subunit mRNA levels, as well as type I collagen mRNA (P < 0.05 for both), but not transforming growth factor-beta mRNA levels (Northern blot analysis), were also positively correlated with mesangial expansion score. We postulate that these observations of correlations between activities of cultured SFs and the rate of progression of DN lesions may be predictive of the risk to develop clinical DN in IDDM, may be in part genetically regulated, and may be of pathogenetic importance.
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PMID:Relationships of cell proliferation and expression of integrin subunits and type I collagen in skin fibroblasts with renal lesions in patients with IDDM. 946