Regulation of filtration rate by glomerular mesangial cells in health and diabetic renal disease.
The rate of renal filtration is in large part responsible for volume and electrolyte balance in an organism. Integral components of the renal glomerulus are the mesangial cells (MCs), excitable renal pericytes that regulate the glomerular filtration rate by modulating the surface area of the capillaries. Similar to vascular smooth muscle, the signal transduction pathways and ion selective channels regulating isotonic and isometric contraction of MCs are dependent on the voltage-gated Ca influx. During the response to contractile agonists, both Cl and nonselective cation channels play critical roles to depolarize the membrane potential and activate Ca channels. The relaxation pathways involve a negative-feedback mechanism that counteracts mesangial contraction by regulating voltage-dependent Ca signaling. Part of the feedback response involves the activation of plasmalemmal K channels, which hyperpolarize the membrane potential and inhibit voltage-gated Ca entry. This calcium- and voltage-activated feedback K (BKCa) channel shares biophysical, pharmacologic, and molecular properties with the BKCa channels identified in brain and muscle, and with the sio gene product as expressed in Xenopus laevis oocytes. Systemic hormones, such as atrial natriuretic peptide, and paracrine factors, such as nitric oxide (NO), use guanosine 3',5'-cyclic monophosphate (GMP) as a second messenger and enhance the gain in this feedback system by decreasing the voltage and Ca activation thresholds for BKCa. Diabetes mellitus is often associated with high rates of glomerular filtration, mesangial expansion, and secretory abnormalities of the basement membrane. NO-mediated increases in negative-feedback regulation of mesangial tone may attribute, in part, to the pathology of hyperfiltration. Stimulation of inducible nitric oxide synthetase in glomerular MCs by inflammatory cytokines is a possible positive-feedback pathway that contributes to further glomerular destruction. In addition, high ambient glucose, through modulation of BKCa activity, facilitates MC relaxation and thus propagates hyperfiltration. Since cellular arachidonic acid is metabolically linked to extracellular glucose, this fatty acid is a possible mediator of the pathologic actions of hyperglycemia. Clarification of the signal transduction pathways and ionic mechanisms regulating the normal and dysfunctional tones of MCs is essential for rational clinical management of glomerular disease and critical to understanding fluid and electrolyte homeostasis.
Stockand
J D
JD
Department of Internal Medicine, University of Texas Medical School at Houston 77030, USA.
Sansom
S C
SC
D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D006801:Humans