Regulation of mesangial cell ion channels by insulin and angiotensin II. Possible role in diabetic glomerular hyperfiltration
| Autor: | Brian N. Ling, D C Eaton, E E Seal |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Male
medicine.medical_specialty Renal glomerulus Glomerular Mesangial Cell medicine.medical_treatment education Calcium-Transporting ATPases Ion Channels Membrane Potentials Rats Sprague-Dawley Chloride Channels Cations Internal medicine medicine Animals Insulin Patch clamp Cells Cultured Receptors Angiotensin Dose-Response Relationship Drug Mesangial cell Terpenes Chemistry Angiotensin II General Medicine Glomerular Mesangium Rats Endocrinology Chloride channel Thapsigargin Calcium Microelectrodes Glomerular hyperfiltration Research Article |
| Zdroj: | Journal of Clinical Investigation. 92:2141-2151 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci116815 |
| Popis: | We used patch clamp methodology to investigate how glomerular mesangial cells (GMC) depolarize, thus stimulating voltage-dependent Ca2+ channels and GMC contraction. In rat GMC cultures grown in 100 mU/ml insulin, 12% of cell-attached patches contained a Ca(2+)-dependent, 4-picosiemens Cl- channel. Basal NPo (number of channels times open probability) was < 0.1 at resting membrane potential. Acute application of 1-100 nM angiotensin II (AII) or 0.25 microM thapsigargin (to release [Ca2+]i stores) increased NPo. In GMC grown without insulin, Cl- channels were rare (4%) and unresponsive to AII or thapsigargin in cell-attached patches, and less sensitive to [Ca2+]i in excised patches. GMC also contained 27-pS nonselective cation channels (NSCC) stimulated by AII, thapsigargin, or [Ca2+]i, but again only when insulin was present. In GMC grown without insulin, 15 min of insulin exposure increased NPo (insulin > or = 100 microU/ml) and restored AII and [Ca2+]i responsiveness (insulin > or = 1 microU/ml) to both Cl- and NSCC. GMC AII receptor binding studies showed a Bmax (binding sites) of 2.44 +/- 0.58 fmol/mg protein and a Kd (binding dissociation constant) of 3.02 +/- 2.01 nM in the absence of insulin. Bmax increased by 86% and Kd was unchanged after chronic (days) insulin exposure. In contrast, neither Kd nor Bmax was significantly affected by acute (15-min) exposure. Therefore, we concluded that: (a) rat GMC cultures contain Ca(2+)-dependent Cl- and NSCC, both stimulated by AII. (b) Cl- efflux and cation influx, respectively, would promote GMC depolarization, leading to voltage-dependent Ca2+ channel activation and GMC contraction. (c) Responsiveness of Cl- and NSCC to AII is dependent on insulin exposure; AII receptor density increases with chronic, but not acute insulin, and channel sensitivity to [Ca2+]i increases with both acute and chronic insulin. (d) Decreased GMC contractility may contribute to the glomerular hyperfiltration seen in insulinopenic or insulin-resistant diabetic patients. |
| Databáze: | OpenAIRE |
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