Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl₂-induced nephrotic syndrome in rats

Abstract

Nielsen. Increased apical targeting of renal ENaC subunits and decreased expression of 11␤HSD2 in HgCl 2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 290: F674 -F687, 2006. First published September 27, 2005 doi:10.1152/ajprenal.00084.2005.-Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl 2-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11␤-hydroxysteroid dehydrogenase (11␤HSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl 2 (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11␤HSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl 2 treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of ␣-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of ␤-ENaC and ␥-ENaC were decreased in the cortex/ OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11␤HSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the ␣-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting

Effects of receptor-mediated endocytosis and tubular protein composition on volume retention in experimental glomerulonephritis

“…The GN groups showed decreased NaPi-IIa and AQP1 abundance and transcription rate, with immunoreactive signals equally reduced in megalinpositive and megalin-deficient proximal epithelia in the megalin-deficient group. These results partly agree with previous work in models of nephrotic syndrome or anti-Thy1 GN (22,33), although the reason for the decreases remains to be established. Functionally, the decrease in AQP1 and consequent reduction in proximal transcellular water passage may activate tubuloglomerular feedback, which prevents inadequate water and NaCl delivery to the distal nephron in AQP1-deficient mice (45).…”

“…Na ϩ /H ϩ exchanger 3 (NHE3)-dependent sodium reabsorption and lysosomal acidification may be affected (7,32,34), and coexpressed transport proteins such as aquaporin-1 (AQP1) and the Na ϩ -P i cotransporter IIa (NaPi-IIa) may be involved (22). Distally, regulation of the Na ϩ -K ϩ -2Cl Ϫ -cotransporter 2 (NKCC2) of thick ascending limbs (TAL) of Henle's loop may be affected as well (32), but the major distal site of retention has formerly been assigned to the collecting ducts (6,29), and recent work has been concentrated on the activation of the epithelial Na ϩ channel (ENaC) in a RAAS-independent way (3,33,38). New perspectives have also come from observations that ENaC subunits are cleaved by proteases, which may increase the open probability of the channel (3,5,13,21,22,25,28,43,48; for a review, see also Ref.…”

Long-term aldosterone treatment induces decreased apical but increased basolateral expression of AQP2 in CCD of rat kidney

“…This could then induce a secondary change in AQP2 localization as described in the medulla (34), although the global cortical osmolality does not change. Finally, increased basolateral expression of AQP2 in the CCD has also been described in nephrotic syndrome, another condition with markedly increased sodium reabsorption in the CCD (16).…”

Mechanisms of ENaC Regulation and Clinical Implications

“…142,143 Increased apical targeting of ENaC subunits is seen in sodium avid states such as certain models of nephrotic syndrome or cirrhosis. 144 …”