ABSTRACT
Aim To observe the effect of mineralocorticoid receptor blocker eplerenone on autophagy in obstructive nephropathy and its mechanism. Methods Totally 36 male Wistar rats were randomly divided into sham-operation group, model group and eplerenone group. The animal models were established with unilarteral urteral obstruction ( UUO). The rats in eplerenone group were treated with eplerenone (100 mg • kg"1 • d"1). The obstructed kidneys were collected lOd after UUO. The expression of NR3C2 was detected by laser confocal microscopy, the expression of serum and glucocorticoid-induced protein kinase 1 ( SGK-1), phosphorylated mammal target of rapamycin (p-mTOR) , autophagy associated gene 5 (Atg5) , Be-clin-1 and microtubular-associated protein 1 light chain 3 (LC3) were detected by immunohistochemistry and Western blot. Results The expression of NR3C2 was detected in cytoplasm of renal tubular distal epithelial cells, but not in nucleus in sham-operation group with laser confocal microscopy. The expression of NR3C2 was enhanced significantly in model group, mainly in nucleus but significantly inhibited in eplerenone group. The immunohistochemistry and Western blot showed that the expressions of SGK-1, Atg5, Beclin-1 and the ratio of LC3 11/I in model group were up-regulated and down-regulated by eplerenone treated group. The expression of p-mTOR was down-regulated in model group compared with sham-operation group and up-regulated in eplerenone group. Conclusions Eplerenone plays a role in reducing autophagy in obstructive nephropathy via inhibiting the activation of mineralocorti-coid receptor.
ABSTRACT
Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.
Subject(s)
Humans , Infant, Newborn , Male , Acidosis , Dehydration , Epithelial Sodium Channels , Failure to Thrive , Hyperkalemia , Hyponatremia , Kidney , Korea , Pseudohypoaldosteronism , Receptors, MineralocorticoidABSTRACT
Pseudohypoaldosteronism type 1 (PHA1) is a rare form of mineralocorticoid resistance characterized in newborns by salt wasting with dehydration, hyperkalemia and failure to thrive. This disease is heterogeneous in etiology and includes autosomal dominant PHA1 owing to mutations of the NR3C2 gene encoding the mineralocorticoid receptor, autosomal recessive PHA1 due to mutations of the epithelial sodium channel (ENaC) gene, and secondary PHA1 associated with urinary tract diseases. Amongst these diseases, autosomal dominant PHA1 shows has manifestations restricted to renal tubules including a mild salt loss during infancy and that shows a gradual improvement with advancing age. Here, we report a neonatal case of PHA1 with a NR3C2 gene mutation (a heterozygous c.2146_2147insG in exon 5), in which the patient showed failure to thrive, hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone levels. This is the first case of pseudohypoaldosteronism type 1 confirmed by genetic analysis in Korea.