American journal of physiology. Renal physiology
-
Am. J. Physiol. Renal Physiol. · Sep 2003
Smad3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells.
Transforming growth factor (TGF)-beta has been associated with fibrogenesis in clinical studies and animal models. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-beta1 in human mesangial cells. In addition to the Smad pathway, it has been suggested that TGF-beta1 could also activate more classical growth factor signaling. ⋯ These data indicate that PKCdelta is activated by TGF-beta1 in human mesangial cells. TGF-beta1-stimulated PKCdelta activity positively regulates Smad transcriptional activity and is required for COL1A2 gene transcription. Thus cross talk among multiple signaling pathways likely contributes to the pathogenesis of glomerular matrix accumulation.
-
Am. J. Physiol. Renal Physiol. · Sep 2003
Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin.
Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of beta- and gamma-epithelial Na+ channel (ENaC) subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. ⋯ Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal Isc compared with control cells and responded to stimulation by aldosterone (10(-6) M) or vasopressin (10(-9) M) with a further increase in Isc. The rates of the initial increases in Isc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na+ absorption in the distal nephron of patients with Liddle's syndrome.
-
Am. J. Physiol. Renal Physiol. · Aug 2003
Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake.
Data suggest that mineralocorticoid selectivity is differentially regulated in epithelial target tissues. We investigated whether the level of dietary NaCl intake influenced the expression and tissue distribution of 11-beta-hydroxysteroid dehydrogenase type 2 (11betaHSD-2), aldosterone receptor (MR), and glucocorticoid receptor (GR) in rat colon, kidney, and cardiovascular tissue. Rats were fed a diet with 0.01 or 3% NaCl for 10 days. ⋯ Inhibition of 11betaHSD-2 activity by carbenoxolone during NaCl restriction stimulated NHE-3 expression in colon. Dexamethasone stimulated NHE-3 both in colon and kidney. These data indicate that mineralocorticoid selectivity is physiologically regulated by NaCl intake at the level of 11betaHSD-2 expression and tissue distribution in the distal colon, but not in the kidney.
-
Am. J. Physiol. Renal Physiol. · Jul 2003
Ammonium transport and pH regulation by K(+)-Cl(-) cotransporters.
The Na(+)-K(+)-Cl(-) cotransporters (NKCCs), which belong to the cation-Cl(-) cotransporter (CCC) family, are able to translocate NH4(+) across cell membranes. In this study, we have used the oocyte expression system to determine whether the K(+)-Cl(-) cotransporters (KCCs) can also transport NH4(+) and whether they play a role in pH regulation. Our results demonstrate that all of the CCCs examined (NKCC1, NKCC2, KCC1, KCC3, and KCC4) can promote NH4(+) translocation, presumably through binding of the ion at the K(+) site. ⋯ Indeed, NKCC2, KCC1, KCC2, and KCC3 are inhibited at intracellular pH <7.5, whereas KCC4 is activated. These results indicate that certain CCC isoforms may be specialized to operate in acidic environments. CCC-mediated NH4(+) transport could bear great physiological implication given the ubiquitous distribution of these carriers.
-
Am. J. Physiol. Renal Physiol. · Jul 2003
Cloning and localization of KCC4 in rabbit kidney: expression in distal convoluted tubule.
Cl-dependent K secretion is a feature of renal distal tubules and collecting ducts. Recent cloning and identification of K-Cl cotransporter proteins led us to search for additional novel KCC isoforms expressed in the renal distal nephron. A human expressed sequence tag (EST) with high homology to KCC1 was identified. ⋯ The distal convoluted tubule and connecting tubule exhibited the highest level of KCC4 immunoreactivity, followed by the medullary thick ascending limb. A low level of immunoreactivity was detected in the proximal tubule and collecting ducts. We postulate that KCC4 mediates potassium and chloride exit from the cell and may play an important role in salt absorption by the distal convoluted tubule.