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Polyol Pathway Mediates High Glucose-Induced Collagen Synthesis in Proximal Tubule

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Polyol Pathway Mediates High Glucose-Induced Collagen Synthesis in Proximal Tubule View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 45 (1994), pp. 659—666 Polyol pathway mediates high glucose-induced collagen synthesis in proximal tubule ANTHONY J. BLEYER, PETER FUMO, EDWARD R. SNIPES, STANLEY GOLDFARB, DAVID A. SIMMONS, and FUAD N. ZIYADEH The Renal-Electrolyte and Hypertension Division, the Diabetes Section, and the Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA Polyol pathway mediates high glucose-induced collagen synthesis in conclusion also supported by evidence from tissue culture proximal tubule. The poiyoi pathway in diabetes is activated in tissues that are not dependent on insulin for glucose uptake. To examine the [6-8]. role of the polyol pathway in renal extracellular matrix accumulation, Recent studies in streptozotocin-induced diabetes mellitus in we incubated murine proximal tubule cells in either normal or high the rat have provided convincing evidence that the early phase glucose concentration in the presence or absence of the aldose reduc- of kidney involvement is characterized by increased expression tase inhibitor sorbinil. Raising medium glucose from 100 to 450 mg/dl of collagen type IV in the proximal tubular epithelium [9]. We for 72 hours increased cell sorbitol levels sevenfold. Addition of 0.4mM sorbinil reduced sorbitol content to virtually undetectable levels ashave previously used proximal tubule epithelial cells main- measured by gas chromatography. Sorbinil (0.1 to 0.2 mM) also reduced tained in continuous cell culture in order to study the direct the secretion of collagens types IV and I in the high glucose concen- effects of high glucose concentration on growth and collagen tration after 48 to 72 hours but had no appreciable effect in the normal synthesis [10—12]. These cells elaborated increased amounts of glucose concentration. Concordantly, 0.1 mrt sorbinil inhibited the high glucose-induced stimulation of al(IV) and a2(I) mRNA levels without collagen types IV and I under the influence of high ambient affecting levels in normal glucose concentration. To study the role ofglucose [10, 11]. Concordantly, increased steady-state mRNA transcriptional activation of collagen genes, we transfected proximal levels for the al chain of type IV collagen and the a2 chain of tubule cells with a chioramphenicol acetyltransferase (CAT) reporter type I collagen were also demonstrated. Using nuclear run-off gene linked to the promoter and regulatory elements of ol(IV) gene. CAT activity increased several-fold in the cells grown in the high versus assays to measure in vitro gene transcription rate [10], and the normal glucose concentration; this transcriptional activation in culture chloramphenicol acetyltransferase (CAT) reporter gene assay media containing high glucose concentration was reduced by treatment [8, 10], collagen gene transcription rates were also enhanced of the cells with 0.1 m sorbinil. Thus, high ambient glucose activates under the influence of high ambient glucose. Thus, elevated the polyol pathway in proximal tubule cells, and may mediate the high glucose concentration stimulated collagen gene transcription in glucose-induced stimulation of gene expression for collagens types IV and 1. For type IV collagen, activation of the polyol pathway may alsoproximal tubule cells, and this effect contributed to increased involve, at least in part, transcriptional activation of cis-acting gene collagen synthesis and secretion. regulatory elements. The cellular mechanisms involved in the high glucose-in- duced transcriptional activation of collagen genes are unclear, but one such mechanism may involve the increased activity of the polyol pathway by high ambient glucose levels. Since its Diabetic nephropathy is characterized by cellular hypertro-identification, the role of the polyol pathway in the myriad phy in both glomerular and tubular compartments, progressivecomplications of diabetes mellitus has been the subject of accumulation of extracellular matrix components in the glomer-intense investigation [13, 14]. Aldose reductase, the first and ular mesangium, and thickening of the glomerular and tubular rate-limiting enzyme in this pathway, catalyzes the NADPH- basement membranes [1—SI. Albeit less well-recognized, pro-dependent reduction of hexose or pentose sugars to their gressive tubulointerstitial fibrosis is also a typical feature of the corresponding sugar alcohols, or polyols [1]. This metabolic disease, particularly when reduction in the glomerular filtrationconversion is of great functional significance in tissues which do rate (GFR) becomes apparent [2, 5]. Although capillary hyper-not require insulin for glucose uptake: the kidney, lens, retina, tension, an abnormal metabolic environment, and genetic pre-and peripheral nerves. Importantly, these organs are also the disposition may all participate in the pathogenesis of diabeticsites of significant diabetic complications. nephropathy, hyperglycemia per se remains an essential factor The role of the poiyol pathway in diabetic nephropathy has that is necessary for the occurrence of the kidney disease, a been the focus of increased attention. Goldfarb et al [15] have shown that sorbinil, an aldose reductase inhibitor, greatly diminished the elevated GFR in short-term streptozotocin- Received for publication July 8, 1993 induced diabetes in rats, presumably by increasing afferent and in revised form October 22, 1993 arteriolar resistance to normal levels. In a six-month random- Accepted for publication October 25, 1993 ized trial of 20 type I normo-albuminuric diabetic subjects, © 1994 by the International Society of Nephrology ponalrestat reduced renal hyperfiltration [16]. Ponalrestat also 659 660 Bleyeret a!: Sorbinil and renal collagen reduced glomerular prostaglandin production and urinary albu-sisted of Dulbecco's modified Eagle medium (DMEM: GIBCO min excretion in diabetic rats without altering GFR [17]. TheLaboratories, Grand Island, New York, USA) containing a long-term effects of polyol pathway inhibition on renal extra-physiologically normal D-glucose concentration of 100 mgldl cellular matrix accumulation have not been uniformly favor-(5.5 mM) supplemented with 10% inactivated fetal calf serum, able. The aldose reductase inhibitor Statil did not reduce the100 U/mI penicillin, 100 g/ml streptomycin and 2 m addi- magnitude of glomerulosclerosis in diabetic rats after seventional L-glutamine. months despite normalization of erythrocyte sorbitol levels with this drug [18]. Neither tolrestat [191 nor ponalrestat [20] Growth conditions for poiyoi measurements and collagen reduced the thickening of the glomerular basement membrane mRNA extraction in six-month old severely diabetic rats. Ponalrestat [21] also had For each experiment, 2 X 106 MCT cells were plated into no effect on whole kidney mRNA encoding the a! chain of typeeach of four 75 cm2 flasks, and the cells were maintained in the IV collagen in severely diabetic rats. However, it should begrowth media for several days until a confluent monolayer was noted that the mRNA for this chain decreased with age in bothachieved. The cells were rested for 24 hours in serum-free normal and untreated diabetic animals [21]. On the other hand,DMEM containing 100 mg/dl D-glucose. The media were then Patel and Boot-Handford [22] showed diminished al(IV)changed to serum-free DMEM containing either 100 or 450 mRNA levels in diabetic animals treated with sorbinil for onemgldl glucose concentration, without or with 0.1 to 0.4 ifiM month. A decrease in width of the glomerular basement mem-sorbinil, and the cells were harvested after two to three days. brane has been reported in long-term diabetic rats fed sorbinilThese relatively high concentrations of sorbinil were chosen in [23]. These varying results may relate to the difficulty inorder to achieve effective high levels of the drug for up to 72 examining the effects of the polyol pathway in whole kidney,hours in culture and to assure maximal inhibition of aldose the likelihood that total inhibition of aldose reductase activityreductase. These doses did not affect cell viability as assessed was not achieved, the differences in duration and severity of grossly by phase-contrast microscopy nor was there significant diabetes, and the characteristics of various animal models. inhibition of cellular proliferation. To further examine the possible role of the polyol pathway in collagen biosynthesis in cultured proximal tubule cells, we have Fructose and sorbitol measurements undertaken a series of experiments showing that high glucose stimulates the activity of the polyol pathway as reflected by Polyols were measured as previously reported [14]. Cell marked intracellular sorbitol accumulation. Both the increasedmonolayers were washed three times with phosphate-buffered sorbitol production and the accompanying increased collagensaline (PBS), and the cells were then lysed with ice-cold biosynthesis were abrogated by treatment with sorbinil. Thusdeionized water. A known amount of alpha-methyl mannose these findings are consistent with the hypothesis that increasedpyranoside was added to each flask before lysis to be used as an activity of the polyol pathway may be involved in mediatinginternal standard for subsequent chromatographic assays. After some of the early distinctive changes of hyperglycemia in thelysis, the cells were
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