HORMONAL INFLUENCES ON THE RENAL MICROVASCULATURE

Summary

Principal Investigator: PAMELA CARMINES
Abstract: Accumulating evidence suggests that renal afferent and efferent arterioles rely on disparate mechanisms to achieve agonist-induced alterations in intracellular Ca2+ concentration ([Ca2+]i). This proposal will examine the hypothesis that renal afferent and efferent arterioles are differentially reliant upon electromechanical coupling (E-MC) mechanisms operative with VMS cells, with afferent arteriolar function being tightly linked to sarcolemmal transmembrane potential (Em) and efferent arteriolar function being relatively independent of Em. If this situation occurs, any disruption of E-MC in the renal microvasculature should result in selective afferent arteriolar dysfunction. We postulate that a pathophysiological disruption of E-MC engenders afferent vasodilation and reduced contractile responsiveness during the hyperfiltration stage of insulin-dependent diabetes mellitus (IDDM). The proposed studies will focus on delineating responses to the primary sodium- and water-retaining peptide hormones, angiotensin II (AngII) and arginine vasopressin (AVP). Intracellularly sequestered fluorescent probes will be utilized to monitor [Ca2+]i, [CI]i., [K+]i and Em responses in afferent and efferent arterioles isolated from rabbit kidney. These studies will determine if afferent and efferent arteriolar responses to agonist activation are differentially dependent on Ca2+ influx and release events, as well as activation of phospholipase C, tyrosine kinase, and protein kinase C. VSM cells isolated from the rat preglomerular microvasculature will be used, together with fluorescent probes and patch clamp techniques, in studies designed to determine the impact of Ca2+-activated K+ channels and Ca2+- activated CI channels on Em and [Ca2+]i during agonist stimulation. Preglomerular VSM cells harvested from streptozocin-treated rats will be used in studies targeting specific aberrations in E-MC during IDDM. A fluorescent dihydropyridine will be used to determine if the number of afferent arteriolar L-type voltage-gated Ca2+ channels (VGCCs) is reduced in IDDM, while patch clamp studies will consider mechanisms that might underlie a functional suppression of VGCCs in preglomerular VSM during IDDM. Other studies will test the postulate that an enhanced hyperpolarizing influence of K+ channels (Ca2+-activated and/or ATP- sensitive) also accompanies IDDM. For all aspects of the proposed work, studies at the cellular level will be complemented by parallel studies detailing the functional impact of the putative signaling events on vasoconstrictor responsiveness in afferent and efferent arterioles of the perfused juxtamedullary microvasculature. We anticipate that these studies will provide unique information detailing cellular events involved in hormonal control of the renal microvasculature, both under normal conditions and during the hyperfiltration stage of IDDM.
Funding Period: 1988-09-15 - 2004-07-31
more information: NIH RePORT

Top Publications

  1. pmc The renal vascular response to diabetes
    Pamela K Carmines
    University of Nebraska College of Medicine, Omaha, Nebraska, USA
    Curr Opin Nephrol Hypertens 19:85-90. 2010
  2. pmc Relative contributions of Ca2+ mobilization and influx in renal arteriolar contractile responses to arginine vasopressin
    Rachel W Fallet
    Dept of Cellular and Integrative Physiology, Univ of Nebraska College of Medicine, 985850 Nebraska Medical Ctr, Omaha, NE 68198 5850, USA
    Am J Physiol Renal Physiol 288:F545-51. 2005
  3. pmc Src family kinase involvement in rat preglomerular microvascular contractile and [Ca2+]i responses to ANG II
    Qi Che
    Dept of Cellular and Integrative Physiology, Univ of Nebraska College of Medicine, 985850 Nebraska Medical Ctr, Omaha, NE 68198 5850, USA
    Am J Physiol Renal Physiol 288:F658-64. 2005

Scientific Experts

Detail Information

Publications3

  1. pmc The renal vascular response to diabetes
    Pamela K Carmines
    University of Nebraska College of Medicine, Omaha, Nebraska, USA
    Curr Opin Nephrol Hypertens 19:85-90. 2010
    ..This review will summarize recent advances (published January 2008 through June 2009) regarding the renal vascular and glomerular functional changes that occur during the early stage of diabetes...
  2. pmc Relative contributions of Ca2+ mobilization and influx in renal arteriolar contractile responses to arginine vasopressin
    Rachel W Fallet
    Dept of Cellular and Integrative Physiology, Univ of Nebraska College of Medicine, 985850 Nebraska Medical Ctr, Omaha, NE 68198 5850, USA
    Am J Physiol Renal Physiol 288:F545-51. 2005
    ..Moreover, the VGCC contribution to AVP-induced renal arteriolar contraction resides primarily in the afferent arteriole...
  3. pmc Src family kinase involvement in rat preglomerular microvascular contractile and [Ca2+]i responses to ANG II
    Qi Che
    Dept of Cellular and Integrative Physiology, Univ of Nebraska College of Medicine, 985850 Nebraska Medical Ctr, Omaha, NE 68198 5850, USA
    Am J Physiol Renal Physiol 288:F658-64. 2005
    ..We conclude that the preglomerular vasoconstriction evoked by ANG II involves rapid c-Src activation with subsequent effects that contribute to the [Ca(2+)](i) response to the peptide...