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An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11 [beta]-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 [mu]M) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding [Na.sup.+]-[K.sup.+]-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models. gene expression; glucocorticoid; renal cystogenesis doi: 10.1152/ajprenal.00574.2009

Background: There are numerous causes of bilateral hyperechoic kidneys. Congenital disorders of glycosylation (CDGs) are a rapidly growing family of inherited disorders due to defects in the synthesis of the glycans of glycoproteins or other glycoconjugates. Objective: To describe renal sonographic abnormalities in CDG type I in infants and children. Material and methods: A retrospective study of renal US in 12 infants and children: 8 CDG-Ia (6 multivisceral forms, 2 neurological forms), 2 CDG-Ib, and 2 CDG-Ix, with detailed functional renal tests in 6. Histology of the kidneys of one 35-week fetus with CDG-Ia was available. Results: Renal US was normal in the two children with the neurological form of CDG-Ia. All patients with the multivisceral form of CDG-Ia or with CDG-Ib showed increased cortical echogenicity, and/or abnormal pyramids (small +/- hyperechoic). The two patients with CDG-Ix showed predominant involvement of the medulla, with inverted corticomedullary differentiation in one. Kidney size was normal in all but two patients. The fetal kidneys exhibited diffuse microcysts arising from the distal tubules. Conclusions: Hyperechoic kidneys are common in CDG-I patients, contrasting with grossly preserved renal function. The US pattern seems to differ slightly according to the type of CDG-I, and is consistent with microcystic changes of the renal parenchyma, which occur prenatally, and may be due to ciliary dysfunction secondary to altered glycosylation of tubular glycoproteins. CDG-I, which remains largely under-diagnosed at present, should be added to the causes of hyperechoic kidneys in children, especially in cases of multivisceral involvement, after ruling out other more frequent causes. Keywords Kidney * Cysts * Congenital disorders of glycosylation * Ultrasound * Children