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“Science is built up of facts,
as a house is with stones. But a collection of facts is no more a science
than a heap of stones is a house.” Henri Poincare
The kidney guards the volume and the composition of the body fluids against
outside influences that would otherwise make life untenable. The machinery
for this is complex and links together vascular function, cellular
metabolism, epithelial transport, diffusive and osmotic fluxes, special
membrane permeabilities, and countercurrent anatomy. Much information about
these components has been catalogued through efforts at dissecting them into
smaller and smaller parts. However, the critical emergent behaviors of the
kidney that govern the body fluids are not apparent from looking at these
individual parts. To achieve the ultimate goal, which is to understand the
human organism, its physiology, and pathophysiology and to use this
understanding to improve human health requires that we explain the
relationships between the parts. In this spirit, a satellite symposium to
the XXXV International Congress of Physiological Sciences convened for two
days in March 2005 on campus at the University of California, San Diego.
The symposium, titled “Coordinating Hemodynamic, Filtration, and
Reabsorptive Functions of the Kidney,” was attended by nearly 100
academicians and post-doctoral fellows, and included formal presentations
from 26 international experts in the fields of kidney hemodynamics,
mathematical modeling, epithelial transport, urinary concentration,
tubuloglomerular feedback (TGF), and blood pressure.
The opening presentation by Peter Harris (Melbourne) addressed a modeling
perspective on reconciling integrative concepts with quantitative data and
demonstrated some early work on the Kidney Simulation Project under
development in Melbourne as a teaching tool.
This was followed by a series of presentations relating to the relationship
between filtered load and proximal tubular reabsorption. NaCl reabsorption
by the proximal tubule involves passive and active transport. The passive
component is driven by a local decrease in mixing entropy achieved through
active removal of glucose and bicarbonate from the tubular fluid. The active
component employs apical anion exchange to raise intracellular chloride
above its equilibrium potential. Peter Aronson (Yale) presented an update on
the apical and ion exchangers responsible for the active component of
proximal chloride reabsorption. Recent evidence is that the
“chloride-formate exchanger” (CFEX), through which apical entry of chloride
occurs, operates in various “modes” allowing chloride uptake in exchange for
either formate or oxalate. Chloride-formate exchange operates in parallel
with NHE3, which provides a pH gradient necessary to recycle formate from
lumen to cell. Chloride-oxalate exchange operates in parallel with a
sulfate-oxalate exchanger and sodium-sulfate co-transporter that don’t
require sodium-hydrogen exchange. A problem remains in that a high basal
rate active chloride transport seems to persist in CFEX knockouts.
Sodium-linked glucose transport is electrogenic. Volker Vallon (UC San
Diego) presented a hypothesis that outward potassium flux through apical
KCNQ1 potassium channels in the proximal tubule serve to offset the negative
lumen voltage that would otherwise accrue and dissipate the free energy
available for additional glucose transport. Supporting evidence was
presented in the form of micropuncture data in mice lacking KCNE1.
Apical sodium-hydrogen exchange (NHE3) is an essential part of the machinery
for active bicarbonate and chloride reabsorption. Since the free energy for
passive chloride reabsorption is derived from active reabsorption of
bicarbonate, NHE3 is also necessary for this. Therefore, an economical way
to tune overall proximal reabsorption is to regulate the abundance and
activity of NHE3. Alicia McDonough (USC) discussed the regulation of
proximal reabsorption by angiotensin II using data obtained during captopril
treatment to show that angiotensin II tonically coaxes NHE3 and
NHE3-associated proteins and cytoskeletal associated proteins away from the
base and toward the tip of apical microvilli.
Glomerulotubular balance (GTB) is a process through which proximal
reabsorption tracks the glomerular filtration rate. Historically, proximal
GTB has been ascribed to physical factors affecting Starling forces or
hydraulic permeabilities and to limited availability of some filtered
solutes such as glucose. But new evidence reveals that changes in tubular
flow velocity, per se, elicit parallel changes in proximal reabsorption by a
mechanosensory mechanism. Increasing the tubular flow velocity applies a
torque to the tips of microvilli, which have long moment arms. This torque
is transduced through the cytoskeleton to increase the activity of NHE3 and
proton ATPase which, in turn, drive sodium bicarbonate reabsorption. This
was discussed by Tong Wang (Yale).
Some have espoused that the traditional approach to describing complex
processes with systems of partial differential equations will be of limited
usefulness to systems biology. Meanwhile, others forge ahead using this
approach. Alan Weinstein (Cornell) discussed his recent success at modeling
epithelial cell homeostasis in the proximal tubule as a linear dynamical
system incorporating 31 variables (concentrations, volumes, pressures) and
24 parameters of interest.
The next series of presentations related to flow and transport beyond the
proximal tubule. One of the discussants, Alan Yu (USC), described the
pore-barrier function of the various claudins, which are essential
components of tight junctions along the nephron.
Several others spoke on matters pertaining to the concentrating mechanism.
It has been 60 years since Henle’s loop was proposed to function as a
countercurrent multiplier. Yet controversy persists over the source of free
energy to run the inner medullary portion. Harold Layton (Duke University)
briefly reviewed several of the hypotheses that have been advanced over the
years and discussed the functional significance of computer-assisted 3-D
reconstructions of the inner medulla based on immunohistochemical labeling
of transport proteins. Mark Knepper (NIH) showed that urine volume becomes a
slave to dietary protein in mice lacking urea transporters in the inner
medullary collecting duct. He also discussed the Schmidt-Nielsen peristaltic
theory of urinary concentration and proposed interstitial hyaluronan as a
mechano-osmotic transducer to store free energy that is supplied to the
papilla by peristaltic contraction of the ureteral pelvic wall.
Leon Moore (SUNY Stony Brook) began with a rhetorical question: “What is the
purpose of modeling the thick ascending limb?” He answered by using a basic
model of TAL transport and backleak combined with TGF to explain complex
features of renal hemodynamics, then noted that these insights could not be
obtained by experimentation alone.
Susan Wall (Emory) pointed out the importance of dietary chloride to
salt-dependent hypertension and showed that non-A type intercalated cells in
the cortical collecting duct reabsorb chloride in response to
mineralocorticoid via upregulation of the apical anion exchanger, pendrin
(Slc26a4). As proof of the importance of this system to homeostasis, the
pendrin deficient mouse is resistant to DOCP-salt hypertension. By contrast,
type A intercalated cells, which predominate in the outer medullary
collecting duct express chloride-bicarbonate exchangers on the basolateral
side and actually secrete chloride when stimulated with mineralocorticoid.
Qualitatively, this latter mechanism must work against chloride homeostasis,
but its effect on blood pressure is too small to detect.
It has been difficult to fully understand the role of endothelin in salt and
water homeostasis because its vascular and tubular effects can’t be affected
one at a time by pharmacology. Donald Kohan (Utah) solved a big part of the
problem by demonstrating salt-sensitive hypertension in a collecting-duct
specific knockout of endothelin-1 (ET-1). Collecting duct ET-1 is thereby
shown to contribute to negative feedback control of the total body salt and
blood pressure, presumably by a paracrine mechanism.
Several talks pertained to the control of renal function, most with emphasis
on the juxtaglomerular apparatus. Laszlo Rosivall (Semmelweis University)
discussed interstitial fluid balance in the extraglomerular mesangium, a
region that has traditionally been viewed as closed-off from the tubule,
vasculature, and lymphatics. The distal afferent arteriole is now shown to
contain fenestrations facing into this area. These provide a pathway for
substances to pass directly between the lumen of the afferent arteriole and
the basolateral side of the macula densa. This opens up the possibility of
bypassing the traditional TGF mechanism for passing information from the
glomerulus to the macula densa by way of Henle’s loop. Armin Kurtz (Regensburg)
discussed the balance between activators and inhibitors of renin release.
Pamela Carmines (Nebraska) discussed the role of tyrosine kinases in renal
arteriolar vasoconstriction.
Warwick Anderson (Monash University) described differential innervation of
renal structures by different subtypes of sympathetic noradrenergic nerves
and hypothesized that differential subtype innervation of pre- and post-glomerular
arterioles could explain why RBF declines during low-grade hypoxia but
glomerular capillary pressure only declines during a severe hypoxia.
Janos Peti-Peterdi (USC) described an intraglomerular precapillary sphincter
which is controlled by the macula densa and which may fatigue to account for
the resetting of TGF during a prolonged stimulus. The traditional way to
describe dynamic autoregulation in the frequency domain is by short-term
Fourier transform. This method lacks resolution, but working with longer
time series doesn’t work because the dynamic properties of physiologic
systems tend to be non-stationary. Ki Chon (SUNY Stony Brook) described a
method for overcoming this problem by defining coherence as a function of
both time and frequency and combining feed-forward and feedback time-variant
coherence functions to describe dynamic RBF autoregulation in the rat.
Jurgen Schnermann (NIH) reviewed several theories about the role of TGF in
salt balance and discussed the merits and shortcomings of several models in
which these theories might be, or have been, tested.
A final session was devoted to a discussion of homeostasis, blood pressure,
and pathophysiology.
P. Darwin Bell (Alabama) described how a single amino acid difference in the
ubiquitous sodium-calcium exchanger affects regulation of the exchanger by
PKC and contributes to the blood pressure phenotype in Dahl SS/SR rats. John
Lorenz (Cincinnati) described a phenomenon of anticipatory salt excretion,
which is mediated by guanylin peptides secreted by the gut as hormones.
Rodger Loutzenhiser (Calgary) described a novel role for myogenic
vasoconstriction in the kidney. The time course of the myogenic response has
led us to think of it as protection against blood pressure disturbances
below 100 mHz. In contrast, Loutzenhiser observed that, while the response
might take 10 seconds to reach steady state, it gets underway within the
time frame of a single cardiac cycle. Furthermore, the response to a fall in
blood pressure is subtly slower than the response to a rise in blood
pressure. As a result, the overall renal vascular resistance will increase
when the pulse pressure increases, irrespective of the mean arterial blood
pressure. This will serve to protect the glomerular capillary against
systolic hypertension, but could also have the deleterious effect of
shifting the renal function curve rightward in those with stiff arteries.
Jane Reckelhoff (Jackson, MS) discussed potential mechanisms for the
rightward shift in the pressure-natriuresis curve after menopause. Kate
Denton (Monash University) discussed the programming of blood pressure in
utero. Judith Miller (Toronto) discussed findings related to renal
hemodynamics and diurnal blood pressure variability in human subjects with
early type I diabetes.
The meeting was closed by Gabby Navar (Tulane) with a theory to reconcile
the mutual culpability of angiotensin and hypertension in injurious renal
remodeling. Reconciliation is required because angiotensin normally varies
as the inverse of blood pressure. According to the theory, deleterious
remodeling occurs when intrarenal angiotensin persists in spite of high
blood pressure. Hypertrophy/proliferation results from additive or
synergistic hypertrophic/proliferative effects of angiotensin and ATP, the
latter being released into the renal interstitium as part of the RBF
autoregulatory mechanism to protect the glomerulus against barotrauma.
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