Maturation of aldose reductase expression in the neonatal rat inner medulla.

Schwartz, George J.; Zavilowitz, Beth; Radice, Antonella; García-Peréz, A.; Sands, Jeff M.

doi:10.1172/jci115991

Cited by 39 publications

(31 citation statements)

References 27 publications

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“…Next, intrarenal spatial distribution of this renal-specific gene was studied in view of the fact that ALRs also are expressed in the kidney (30). The ALR2 is expressed in the mesangial cells where it is involved in the pathophysiology of the glomerulus in diabetes (31), and it is also present in the medulla where it is believed to serve as an osmolyte regulator (32). Unlike the ALRs, both mRNA and protein expression of this novel gene were confined to the cortical tubules and not in the glomeruli.…”

Section: Discussionmentioning

confidence: 99%

Identification of a renal-specific oxido-reductase in newborn diabetic mice

Yang

Dixit

Wada

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Aldose reductase (ALR2), a NADPH-dependent aldo-keto reductase (AKR), is widely distributed in mammalian tissues and has been implicated in complications of diabetes, including diabetic nephropathy. To identify a renal-specific reductase belonging to the AKR family, representational difference analyses of cDNA from diabetic mouse kidney were performed. A full-length cDNA with an ORF of 855 nt and yielding a Ϸ1.5-kb mRNA transcript was isolated from a mouse kidney library. Human and rat homologues also were isolated, and they had Ϸ91% and Ϸ97% amino acid identity with mouse protein. In vitro translation of the cDNA yielded a protein product of Ϸ33 kDa. Northern and Western blot analyses, using the cDNA and antirecombinant protein antibody, revealed its expression exclusively confined to the kidney. Like ALR2, the expression was up-regulated in diabetic kidneys. Its mRNA and protein expression was restricted to renal proximal tubules. The gene neither codistributed with Tamm-Horsfall protein nor aquaporin-2. The deduced protein sequence revealed an AKR-3 motif located near the N terminus, unlike the other AKR family members where it is confined to the C terminus. Fluorescence quenching and reactive blue agarose chromatography studies revealed that it binds to NADPH with high affinity (KdNADPH ‫؍‬ 66.9 ؎ 2.3 nM). This binding domain is a tetrapeptide (Met-Ala-Lys-Ser) located within the AKR-3 motif that is similar to the other AKR members. The identified protein is designated as RSOR because it is renal-specific with properties of an oxido-reductase, and like ALR2 it may be relevant in the renal complications of diabetes mellitus.diabetes mellitus ͉ diabetic nephropathy R enal complications are a common manifestation of diabetes mellitus. Characteristics of these complications are an increase of extracellular matrix (ECM) proteins, i.e., type I and type IV collagens and decorin and fibronectin, synthesized by glomerular, tubular, and interstitial cells (1). The increase in ECM may be multifactorial, but recent studies have narrowed it down to two or three pathogenetic mechanisms that are affected by hyperglycemia. The hyperglycemia may increase the mRNA expression and bioactivity of certain cytokines that modulate the synthesis of various ECM proteins, e.g., transforming growth factor ␤ (2, 3). Nonenzymatic glycation is another mechanism by which various Amadori intermediaries lead to the generation of advanced glycation products (AGEs). The AGEs further crosslink the glycated proteins with one another and render them extremely resistant to proteolytic degradation, resulting in an accumulation of ECM in the kidney (4). Such an AGE-mediated cross-linking process is not restricted to the kidney tissue proteins alone, but it affects other tissue proteins as well, e.g., ocular lens crystallins (5, 6). Another mechanism that is also relevant to diabetic nephropathy is the polyol pathway, which consists of two major reactions. First, glucose is reduced by aldose reductase (ALR2) to sorbitol by using NADPH as the hydrogen...

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Section: Discussionmentioning

confidence: 99%

Identification of a renal-specific oxido-reductase in newborn diabetic mice

Yang

Dixit

Wada

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…PCR product identity was also confirmed by direct double-stranded sequencing. To control for the RT step and RNA stability, RT-PCR was also done for the housekeeping gene malate dehydrogenase (MDH) using published oligonucleotide primer sequences (18). The PCR temperature profile for MDH was identical to that described above for COX-1.…”

Section: Reverse Transcription-polymerase Chain Reaction (Rt-pcr) Assaymentioning

confidence: 99%

Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium.

Jun¹,

Chen²,

Pace³

et al. 1998

J. Clin. Invest.

120

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Prostacyclin (PGI 2 ) is a key mediator of pulmonary vasodilation in the perinatal period and its synthesis in the pulmonary vasculature increases markedly during late gestation due to enhanced expression of the rate-limiting enzyme cyclooxygenase-1 (COX-1). The hormone estrogen may play a role in COX-1 upregulation since fetal estrogen levels rise dramatically during late gestation and estrogen enhances PGI 2 synthesis in nonpulmonary vascular cells. We therefore studied the direct effects of estrogen on COX-1 expression in ovine fetal pulmonary artery endothelial cells (PAEC). Exposure to estradiol-17 ␤ (E 2 ␤ , 10 Ϫ 10 to 10 Ϫ 6 M) caused a dose-related increase in COX-1 mRNA expression that was evident after 48 h and maximal at 10 Ϫ 8 M (fourfold increase). COX-1 mRNA stability was unchanged, suggesting that the upregulation is mediated at the level of transcription. E 2 ␤ treatment (10 Ϫ 8 M for 48 h) also caused a threefold increase in COX-1 protein expression and a threefold increase in PGI 2 synthesis stimulated by bradykinin, the calcium ionophore A23187, or arachidonic acid. The estrogen receptor (ER) antagonist ICI 182,780 fully reversed the effects of the hormone on COX-1 protein expression and on arachidonic acid-stimulated PGI 2 synthesis, and ER expression was evident in the PAEC by immunoblot analysis. These findings indicate that physiologic levels of estrogen cause upregulation of COX-1 expression and PGI 2 synthesis in fetal PAEC via activation of PAEC ER. This process may play a critical role in optimizing the capacity for PGI 2 -mediated pulmonary vasodilation at birth, and it may also be involved in estrogen responsiveness in other vascular beds. ( J.

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“…In addition, dramatic increases in aldose reductase mRNA and activity have been demonstrated in the developing rat lens and kidney, suggesting that aldose reductase is highly regulated during lens fiber differentiation (23) and during maturation of the inner medulla in rats (24). The induction of aldose reductase gene expression in neonatal rat kidney is attributed to a so far undefined developmental signal rather than to changes in urinary osmolality since the induction occurs before the maturation of the urinary concentration mechanism is completed (24).…”

Section: Methodsmentioning

confidence: 99%

Characterization of the osmotic response element of the human aldose reductase gene promoter.

Ruepp

Bohren

Gabbay

1996

Proc. Natl. Acad. Sci. U.S.A.

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Aldose reductase (EC 1.1.1.21) catalyzes the NADPH-mediated conversion of glucose to sorbitol. The hyperglycemia of diabetes increases sorbitol production primarily through substrate availability and is thought to contribute to the pathogenesis of many diabetic complications. Increased sorbitol production can also occur at normoglycemic levels via rapid increases in aldose reductase transcription and expression, which have been shown to occur upon exposure of many cell types to hyperosmotic conditions. The induction of aldose reductase transcription and the accumulation of sorbitol, an organic osmolyte, have been shown to be part of the physiological osmoregulatory mechanism whereby renal tubular cells adjust to the intraluminal hyperosmolality during urinary concentration. Previously, to explore the mechanism regulating aldose reductase levels, we partially characterized the human aldose reductase gene promoter present in a 4.2-kb fragment upstream of the transcription initiation start site. A fragment (-192 to +31 bp) was shown to contain several elements that control the basal expression of the enzyme. In this study, we examined the entire 4.2-kb human AR gene promoter fragment by deletion mutagenesis and transfection studies for the presence of osmotic response enhancer elements. An 11-bp nucleotide sequence (TGGAAAATTAC) was located 3.7 kb upstream ofthe transcription initiation site that mediates hypertonicity-responsive enhancer activity. This osmotic response element (ORE) increased the expression of the chloramphenicol acetyltransferase reporter gene product 2-fold in transfected HepG2 cells exposed to hypertonic NaCl media as compared with isoosmotic media. A more distal homologous sequence is also described; however, this sequence has no osmotic enhancer activity in transfected cells. Specific ORE mutant constructs, gel shift, and DNA fragment competition studies confirm the nature of the element and identify specific nucleotides essential for enhancer activity. A plasmid construct containing three repeat OREs and a heterologous promoter increased expression 8-fold in isoosmotic media and an additional 4-fold when the transfected cells are subjected to hyperosmotic stress (total "30-fold). These findings will permit future studies to identify the transcription factors involved in the normal regulatory response mechanism to hypertonicity and to identify whether and how this response is altered in a variety of pathologic states, including diabetes.Aldose reductase (EC 1.1.1.21) catalyzes the NADPHmediated reduction of a variety of carbonyl compounds to their respective alcohols with a wide range of catalytic efficiencies (1). The conversion of D-glucose to sorbitol constitutes the first step of the polyol pathway, an accessory pathway of glucose metabolism that converts glucose to fructose. The catalytic efficiency of aldose reductase for D-glucose (1) is relatively low and is reflected by a Km(Dglucose) of 100 mM, a substrate concentration that is 20-fold higher than prevailing normal glycemic...

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Maturation of aldose reductase expression in the neonatal rat inner medulla.

Cited by 39 publications

References 27 publications

Identification of a renal-specific oxido-reductase in newborn diabetic mice

Identification of a renal-specific oxido-reductase in newborn diabetic mice

Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium.

Characterization of the osmotic response element of the human aldose reductase gene promoter.

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