Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Nov;92(5):2141–2151. doi: 10.1172/JCI116815

Regulation of mesangial cell ion channels by insulin and angiotensin II. Possible role in diabetic glomerular hyperfiltration.

B N Ling 1, E E Seal 1, D C Eaton 1
PMCID: PMC288392  PMID: 7693757

Abstract

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.

Full text

PDF
2141

Images in this article

2149Image
on p.2149

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bagdade J. D., Bierman E. L., Porte D., Jr The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest. 1967 Oct;46(10):1549–1557. doi: 10.1172/JCI105646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bank N. Mechanisms of diabetic hyperfiltration. Kidney Int. 1991 Oct;40(4):792–807. doi: 10.1038/ki.1991.277. [DOI] [PubMed] [Google Scholar]
  3. Baró I., Eisner D. A. The effects of thapsigargin on [Ca2+]i in isolated rat mesenteric artery vascular smooth muscle cells. Pflugers Arch. 1992 Jan;420(1):115–117. doi: 10.1007/BF00378652. [DOI] [PubMed] [Google Scholar]
  4. Bevan S., Gray P. T., Ritchie J. M. A calcium-activated cation-selective channel in rat cultured Schwann cells. Proc R Soc Lond B Biol Sci. 1984 Sep 22;222(1228):349–355. doi: 10.1098/rspb.1984.0068. [DOI] [PubMed] [Google Scholar]
  5. Chansel D., Czekalski S., Pham P., Ardaillou R. Characterization of angiotensin II receptor subtypes in human glomeruli and mesangial cells. Am J Physiol. 1992 Mar;262(3 Pt 2):F432–F441. doi: 10.1152/ajprenal.1992.262.3.F432. [DOI] [PubMed] [Google Scholar]
  6. Colquhoun D., Neher E., Reuter H., Stevens C. F. Inward current channels activated by intracellular Ca in cultured cardiac cells. Nature. 1981 Dec 24;294(5843):752–754. doi: 10.1038/294752a0. [DOI] [PubMed] [Google Scholar]
  7. Craelius W., el-Sherif N., Palant C. E. Stretch-activated ion channels in cultured mesangial cells. Biochem Biophys Res Commun. 1989 Mar 15;159(2):516–521. doi: 10.1016/0006-291x(89)90023-5. [DOI] [PubMed] [Google Scholar]
  8. Dunlop M. E., Larkins R. G. Insulin-dependent contractility of glomerular mesangial cells in response to angiotensin II, platelet-activating factor and endothelin is attenuated by prostaglandin E2. Biochem J. 1990 Dec 15;272(3):561–568. doi: 10.1042/bj2720561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fabiato A. Computer programs for calculating total from specified free or free from specified total ionic concentrations in aqueous solutions containing multiple metals and ligands. Methods Enzymol. 1988;157:378–417. doi: 10.1016/0076-6879(88)57093-3. [DOI] [PubMed] [Google Scholar]
  10. Farese R. V. Phospholipid signaling systems in insulin action. Am J Med. 1988 Nov 28;85(5A):36–43. doi: 10.1016/0002-9343(88)90396-8. [DOI] [PubMed] [Google Scholar]
  11. Foidart J., Sraer J., Delarue F., Mahieu P., Ardaillou R. Evidence for mesangial glomerular receptors for angiotensin II linked to mesangial cell contractility. FEBS Lett. 1980 Dec 1;121(2):333–339. doi: 10.1016/0014-5793(80)80375-9. [DOI] [PubMed] [Google Scholar]
  12. Haneda M., Kikkawa R., Maeda S., Togawa M., Koya D., Horide N., Kajiwara N., Shigeta Y. Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation. Kidney Int. 1991 Aug;40(2):188–194. doi: 10.1038/ki.1991.199. [DOI] [PubMed] [Google Scholar]
  13. Hassid A., Pidikiti N., Gamero D. Effects of vasoactive peptides on cytosolic calcium in cultured mesangial cells. Am J Physiol. 1986 Dec;251(6 Pt 2):F1018–F1028. doi: 10.1152/ajprenal.1986.251.6.F1018. [DOI] [PubMed] [Google Scholar]
  14. Hayashi K., Epstein M., Loutzenhiser R., Forster H. Impaired myogenic responsiveness of the afferent arteriole in streptozotocin-induced diabetic rats: role of eicosanoid derangements. J Am Soc Nephrol. 1992 May;2(11):1578–1586. doi: 10.1681/ASN.V2111578. [DOI] [PubMed] [Google Scholar]
  15. Kreisberg J. I. Insulin requirement for contraction of cultured rat glomerular mesangial cells in response to angiotensin II: possible role for insulin in modulating glomerular hemodynamics. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4190–4192. doi: 10.1073/pnas.79.13.4190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kremer S. G., Zeng W., Sridhara S., Skorecki K. L. Multiple signaling pathways for Cl(-)-dependent depolarization of mesangial cells: role of Ca2+, PKC, and G proteins. Am J Physiol. 1992 Apr;262(4 Pt 2):F668–F678. doi: 10.1152/ajprenal.1992.262.4.F668. [DOI] [PubMed] [Google Scholar]
  17. Kurokawa K., Okuda T. Calcium-activated chloride conductance of mesangial cells. Kidney Int Suppl. 1990 Nov;30:S48–S50. [PubMed] [Google Scholar]
  18. Levitan I. B. Phosphorylation of ion channels. J Membr Biol. 1985;87(3):177–190. doi: 10.1007/BF01871217. [DOI] [PubMed] [Google Scholar]
  19. Ling B. N., Kokko K. E., Eaton D. C. Inhibition of apical Na+ channels in rabbit cortical collecting tubules by basolateral prostaglandin E2 is modulated by protein kinase C. J Clin Invest. 1992 Oct;90(4):1328–1334. doi: 10.1172/JCI115998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marcus D. C., Takeuchi S., Wangemann P. Ca(2+)-activated nonselective cation channel in apical membrane of vestibular dark cells. Am J Physiol. 1992 Jun;262(6 Pt 1):C1423–C1429. doi: 10.1152/ajpcell.1992.262.6.C1423. [DOI] [PubMed] [Google Scholar]
  21. Marsden P. A., Brenner B. M. Nitric oxide and endothelins: novel autocrine/paracrine regulators of the circulation. Semin Nephrol. 1991 Mar;11(2):169–185. [PubMed] [Google Scholar]
  22. Marty A., Tan Y. P., Trautmann A. Three types of calcium-dependent channel in rat lacrimal glands. J Physiol. 1984 Dec;357:293–325. doi: 10.1113/jphysiol.1984.sp015501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Marunaka Y., Eaton D. C. Chloride channels in the apical membrane of a distal nephron A6 cell line. Am J Physiol. 1990 Feb;258(2 Pt 1):C352–C368. doi: 10.1152/ajpcell.1990.258.2.C352. [DOI] [PubMed] [Google Scholar]
  24. Marunaka Y., Eaton D. C. Effects of insulin and phosphatase on a Ca2(+)-dependent Cl- channel in a distal nephron cell line (A6). J Gen Physiol. 1990 May;95(5):773–789. doi: 10.1085/jgp.95.5.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Marunaka Y., Eaton D. C. Effects of vasopressin and cAMP on single amiloride-blockable Na channels. Am J Physiol. 1991 May;260(5 Pt 1):C1071–C1084. doi: 10.1152/ajpcell.1991.260.5.C1071. [DOI] [PubMed] [Google Scholar]
  26. Maruyama Y., Moore D., Petersen O. H. Calcium-activated cation channel in rat thyroid follicular cells. Biochim Biophys Acta. 1985 Dec 5;821(2):229–232. doi: 10.1016/0005-2736(85)90091-4. [DOI] [PubMed] [Google Scholar]
  27. Maruyama Y., Peterson O. H. Single-channel currents in isolated patches of plasma membrane from basal surface of pancreatic acini. Nature. 1982 Sep 9;299(5879):159–161. doi: 10.1038/299159a0. [DOI] [PubMed] [Google Scholar]
  28. Matsunaga H., Yamashita N., Miyajima Y., Okuda T., Chang H., Ogata E., Kurokawa K. Ion channel activities of cultured rat mesangial cells. Am J Physiol. 1991 Nov;261(5 Pt 2):F808–F814. doi: 10.1152/ajprenal.1991.261.5.F808. [DOI] [PubMed] [Google Scholar]
  29. Menè P., Cinotti G. A., Pugliese F. Signal transduction in mesangial cells. J Am Soc Nephrol. 1992 Apr;2(10 Suppl):S100–S106. doi: 10.1681/ASN.V210s100. [DOI] [PubMed] [Google Scholar]
  30. Mené P., Simonson M. S., Dunn M. J. Phospholipids in signal transduction of mesangial cells. Am J Physiol. 1989 Mar;256(3 Pt 2):F375–F386. doi: 10.1152/ajprenal.1989.256.3.F375. [DOI] [PubMed] [Google Scholar]
  31. Mené P., Simonson M. S., Dunn M. J. Physiology of the mesangial cell. Physiol Rev. 1989 Oct;69(4):1347–1424. doi: 10.1152/physrev.1989.69.4.1347. [DOI] [PubMed] [Google Scholar]
  32. Nelson M. T., Patlak J. B., Worley J. F., Standen N. B. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol. 1990 Jul;259(1 Pt 1):C3–18. doi: 10.1152/ajpcell.1990.259.1.C3. [DOI] [PubMed] [Google Scholar]
  33. Nishio M., Tsukahara H., Hiraoka M., Sudo M., Kigoshi S., Muramatsu I. Calcium channel current in cultured rat mesangial cells. Mol Pharmacol. 1993 Jan;43(1):96–99. [PubMed] [Google Scholar]
  34. Palant C. E., Ross M. J. Role of ionic currents in the physiological response to angiotensin II. Ren Physiol Biochem. 1991 Jul-Oct;14(4-5):186–198. doi: 10.1159/000173404. [DOI] [PubMed] [Google Scholar]
  35. Ray P. E., Aguilera G., Kopp J. B., Horikoshi S., Klotman P. E. Angiotensin II receptor-mediated proliferation of cultured human fetal mesangial cells. Kidney Int. 1991 Oct;40(4):764–771. doi: 10.1038/ki.1991.273. [DOI] [PubMed] [Google Scholar]
  36. Sturgess N. C., Hales C. N., Ashford M. L. Calcium and ATP regulate the activity of a non-selective cation channel in a rat insulinoma cell line. Pflugers Arch. 1987 Aug;409(6):607–615. doi: 10.1007/BF00584661. [DOI] [PubMed] [Google Scholar]
  37. Takahashi T., Neher E., Sakmann B. Rat brain serotonin receptors in Xenopus oocytes are coupled by intracellular calcium to endogenous channels. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5063–5067. doi: 10.1073/pnas.84.14.5063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Takenaka T., Epstein M., Forster H., Landry D. W., Iijima K., Goligorsky M. S. Attenuation of endothelin effects by a chloride channel inhibitor, indanyloxyacetic acid. Am J Physiol. 1992 May;262(5 Pt 2):F799–F806. doi: 10.1152/ajprenal.1992.262.5.F799. [DOI] [PubMed] [Google Scholar]
  39. Taleb O., Feltz P., Bossu J. L., Feltz A. Small-conductance chloride channels activated by calcium on cultured endocrine cells from mammalian pars intermedia. Pflugers Arch. 1988 Oct;412(6):641–646. doi: 10.1007/BF00583766. [DOI] [PubMed] [Google Scholar]
  40. Wolf G., Thaiss F., Schoeppe W., Stahl R. A. Angiotensin II-induced proliferation of cultured murine mesangial cells: inhibitory role of atrial natriuretic peptide. J Am Soc Nephrol. 1992 Dec;3(6):1270–1278. doi: 10.1681/ASN.V361270. [DOI] [PubMed] [Google Scholar]
  41. Xuan Y. T., Wang O. L., Whorton A. R. Thapsigargin stimulates Ca2+ entry in vascular smooth muscle cells: nicardipine-sensitive and -insensitive pathways. Am J Physiol. 1992 May;262(5 Pt 1):C1258–C1265. doi: 10.1152/ajpcell.1992.262.5.C1258. [DOI] [PubMed] [Google Scholar]
  42. Yellen G. Single Ca2+-activated nonselective cation channels in neuroblastoma. Nature. 1982 Mar 25;296(5855):357–359. doi: 10.1038/296357a0. [DOI] [PubMed] [Google Scholar]
  43. Yu Y. M., Lermioglu F., Hassid A. Modulation of Ca by agents affecting voltage-sensitive Ca channels in mesangial cells. Am J Physiol. 1989 Dec;257(6 Pt 2):F1094–F1099. doi: 10.1152/ajprenal.1989.257.6.F1094. [DOI] [PubMed] [Google Scholar]
  44. von Tscharner V., Prod'hom B., Baggiolini M., Reuter H. Ion channels in human neutrophils activated by a rise in free cytosolic calcium concentration. 1986 Nov 27-Dec 3Nature. 324(6095):369–372. doi: 10.1038/324369a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES