DISCUSSION
Acute regulation of sodium pump activity
There is a burgeoning literature on mechanisms responsible for short term regulation
of Na,K-ATPase activity (Aperia et al, 1996, 1994; Boron et al, 1997; Bertorello & Katz,
1993). Pathways linked to both generation of protein kinase C (PKC) and/or cyclic-AMP
dependent protein kinase A are postulated to regulate Na,K-ATPase activity by
changing the α catalytic subunit phosphorylation status. However, phosphorylation has
been associated with both decreased activity (Aperia et al, 1994; Chibalin et al, 1995;
Middleton et al, 1993; Satoh et al, 1993a, 1993b), and increased activity (Carranza et al,
1996a, 1996b), and no change in activity (Boron et al, 1997). There is also evidence that
PKC causes a withdrawal of sodiuln pumps from the basolateral membranes even if
there is mutation of the phosphorylation site (Boron et al, 1997). Proximal tubule
Na,K-ATPase activity is also inhibited (whether directly or indirectly is not known) by
activation of phospholipase A2 which stimulates production of arachidonate metabolites
of cytochrome P-450 such as 20-HETE (Aperia et al, 1996; Nowicki et al, 1997;
Ominato et al, 1996). Although the precise signaling mechanisms re main to be
elucidated for the responses to altered blood pressure, our results indicate that the
inhibition of the sodium pump activity in PT is due to structural modification of the
pump itself or an associated regulator, rather than solely mediated by trafficking of
active pumps to a new location, because the data demonstrate. significant changes in
total ATPase activity that persist through membrane fractionation and phase partitioning,
and our results implicate a role of cat P45O aa metabolism to 20-HETE in the
response(Zhang et al, 1998)
Altered natriuretic responses in hypertension
As discussed in the introduction, an altered natriuretic response to an elevation in
blood pressure is the hallmark of hypertension. The Spontaneously Hypertensive Rat
(SHR)has numerous renal defects that could account for the development of
hypertension. In regards to this project, the PT of SHR fail to respond normally to the
natriuretic hormone dopamine (Kinoshita et al, 1989), and they have enhanced
tubuloglomerular feedback (TGF) response (reviewed in Cowley & Roman, 1997). Our
results indicate a distribution of apical sodium transportes in SHR is the same as in
acutely hypertensive SD (Magyar et al, 1997),
In summary, our findings to date suggest that the dynamic regulation of proximal
tubule and loop of Henle sodium transport by fluctuations in blood pressure may be
mediated by changes in sodium transporter characteristics at both the apical and
basolateral membranes: 1) by reversible inhibition of basolateral Na,K-ATPase activity
in the PT and activation in the TALH, and 2) relocation of a set of apical proteins,
including NHE-3 and NaPi, consistent with redistribution to intermicrovillar cleft region
and/or internalization to endosomal pools in the PT. The reciprocal modulation of
Na,K-ATPase activity in PT and TALH contributes the driving force for activating
TGF, while minimizing changes in delivery of salt and water to the hormone sensitive
distal nephron.
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