The rising tide of diabetic nephropathy (DN) is arguably the most challenging clinical problem confronting nephrologists at the beginning of the new century. Central to the development of novel diagnostic and therapeutic strategies will be the elucidation of the molecular events that drive this complex disease. In this review, we briefly discuss the major growth factors and cytokines identified as mediators of tissue injury in DN in the ‘pre-gene subtraction’ era. We then highlight the remarkable array of new molecular players already identified with the introduction of gene subtraction techniques, such as differential-display PCR, suppression-subtractive hybridization, and nucleotide micro-arrays, and discuss the likely impact of these technologies going forward. Finally, we summarize the current knowledge on the cell signalling events triggered by high glucose levels that influence gene expression in DN and that represent additional therapeutic targets in this setting.

1.
UK Prospective Diabetes Study Group (UKPDS): Intensive blood glucose control with sulphonylureas or insulin compared to conventional treatment and the risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–853.
2.
The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-treated diabetes mellitus. N Engl J Med 1993;329:977–986.
3.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456–1462.
4.
Cortes P, Zhao X, Riser BL, Narins RG: Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy. Kidney Int 1997;51:57–68.
5.
Wolf G, Sharma K, Ericksen M, Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGFβ1. Kidney Int 1980;42:647–656.
6.
Young BA, Johnson RJ, Alpers CE, Eng E, Gordon K, Floege J, Couser WG, Seidel K: Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int 1995;47:935–944.
7.
Wolf G: Cell cycle regulation in diabetic nephropathy. Kidney Int Supppl 2000;77:59–66.
8.
Kaname S, Uchida S, Ogato E, Kurokawa A: Autocrine secretion of transforming growth factor-β in cultured rat mesangial cells. Kidney Int 1992;42:1319–1327.
9.
Wolf G, Sharma K, Ericksen M, Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β1. Kidney Int 1992;42:647–656.
10.
Rocco MV, Chen Y, Goldfarb S, Ziyadeh FN: Elevated glucose levels stimulate transforming growth factor-beta gene expression and bioactivity in murine proximal tubule cell culture. Kidney Int 1992;41:107–114.
11.
Riser BL, Ladson-Wofford S, Sharba A, Cortes P, Drake K, Guérin CJ, Yee J, Choi ME, Segarini PR, Narins RG: TGF-beta receptor expression and binding in rat mesangial cells: Modulation by glucose and cyclic mechanical strain. Kidney Int 1999;56:428–439.
12.
Nakamura T, Fukui M, Ebihara I, Osada S, Nagaoka I, Tomino Y, Koide H: mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 1993;42:450–456.
13.
Shankland SJ, Scholey JW: Expression of transforming growth factor-β1 during diabetic renal hypertrophy. Kidney Int 1994;46:430–442.
14.
Ziyadeh FN, Han DC: Involvement of transforming growth factor-β and its receptors in the pathogenesis of diabetic nephropathy. Kidney Int Suppl 1997;60:7–11.
15.
Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE: Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: Role of the renin-angiotensin system. Kidney Int 1997;51:1553–1567.
16.
McGowan TA, Sharma K: Regulation of inositol 1,4,5-triphosphate receptors by transforming growth factor-β: Implications for vascular dysfunction in diabetes. Kidney Int Suppl 2000;77:99–103.
17.
Zhou Z, Tepel M, Neusser M, Zidek W: Transforming growth factor beta 1 modulates angiotensin II-induced calcium influx in vascular smooth muscle. Eur J Clin Invest 1995;25:317–321.
18.
Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R: TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int 1999;55:1704–1712.
19.
Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY: Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 1999;56:1455–1467.
20.
Okada H, Danoff TM, Kalluri R, Neilson EG: Early role of Fsp-1 in epithelial-mesenchymal transformation. Am J Physiol 1997;273:F563–F574.
21.
Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K: Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci USA 2000;97:8015–8020.
22.
Leehey DJ, Singh AK, Alavi N, Singh R: Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl 2000;77:93–98.
23.
Amemaya S, Ishihara T, Higashida K, Kusano S, Ohyama K, Kato K: Altered synthesis of renin in patients with insulin-dependent diabetes: Plasma prorenin as a marker predicting the evolution of nephropathy. Diabetes Res Clin Pract 1990;10:15–122.
24.
Burns KD: Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis. 2000;36:449–467.
25.
Wolf G, Haberstroh U, Neilson EG: Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 1992;140:95–107.
26.
Homma T, Hoover RL, Ichikawa I, Harris RC: Angiotensin II induces hypertrophy and stimulates collagen production in cultured rat glomerular mesangial cells (abstract). Clin Res 1990;38:358.
27.
Wolf G, Haberstroh U, Nielson EG: Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 1992;140:95–107.
28.
Wolf G, Zahner G, Mondorf U, Schoeppe W, Stahl RAK: Angiotensin II stimulates cellular hypertrophy of LLC-PK1 cells through the AT1 receptor. Nephrol Dial Transplant 1993;8:128–133.
29.
Wolf G, Killen PD, Neilson EG: Intracellular signalling of transcription and secretion of type IV collagen after angiotensin II-induced cellular hypertrophy in cultured proximal tubular cells. Cell Regul 1991;2:219–227.
30.
Nahman NS Jr, Leonhart KL, Cosio FG, Hebert CL: Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells. Kidney Int 1992;41:396–402.
31.
Ayo SH, Radnik RA, Glass WF 2nd, Garoni JA, Rampt ER, Appling DR, Kreisberg JI: Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. Am J Physiol 1991;260:F185–F191.
32.
Wolf G, Ziyadeh FN: The role of angiotensin II in diabetic nephropathy: Emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 1997;29:153–163.
33.
Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, Haverty TP: High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule. Am J Physiol 1990;259:F704–F714.
34.
Flyvberg A, Gronbaek H, Bak M, Nielsen B, Christiansen T, Hill C, Logan A, Orskov H: Diabetic kidney disease: The role of growth factors. Nephrol Dial Transplant 1998;13:1104–1107.
35.
Abboud HA: Growth factors and diabetic nephropathy: An overview. Kidney Int Suppl 1997;60:3–6.
36.
Werner H, Shen-Orr Z, Stannard B, Burguera B, Roberts CT Jr, LeRoith D: Experimental diabetes increases insulin-like growth factor I and II receptor concentration and gene expression in kidney. Diabetes 1990;39:1490–1497.
37.
Oemar BS, Foellmer HG, Hodgdon-Anandant L, Rosenzweig SA: Regulation of insulin-like growth factor 1 receptors in diabetic mesangial cells. J Biol Chem 1991;266:2369–2373.
38.
Miyatake N, Shikata K, Wada J, Sugimoto H, Takahashi S, Makino H: Differential distribution of insulin-like growth factor-1 and insulin-like growth factor binding proteins in experimental diabetic rat kidney. Nephron 1999;81:317–323.
39.
Verotti A, Cieri F, Petitti MT, Morgese G, Chiarelli F: Growth hormone and IGF-1 in diabetic children with and without microalbuminuria. Diabetes Nutr Metab 1999;12:271–276.
40.
Sugimoto H, Shikata K, Makino H, Ota K, Ota Z: Up-regulation of insulin-like growth factor receptor gene in experimental diabetic rat glomeruli. J Diabetes Complications 1995;9:262–264.
41.
Schreiber BD, Hughes ML, Groggel GC: Insulin-like growth factor-1 stimulates production of mesangial cell matrix components. Clin Nephrol 1995;43:368–374.
42.
Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP: High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. Am J Pathol 1996;149:2095–2106.
43.
Nakamura T, Fukui M, Ebihara I, Osada S, Nagaoka I, Tomino Y, Koide H: mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 1993;42:450–456.
44.
Fagerudd JA, Groop PH, Honkanen E, Teppo AM, Gronhagen-Riska C: Urinary excretion of TGF-beta 1, PDGF BB and fibronectin in insulin-dependent diabetes mellitus patients. Kidney Int Suppl 1997;63:195–197.
45.
Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ: Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 1992;89:2873–2877.
46.
Fisher DA, Salido EC, Barajase L: Epidermal growth factor and the kidney. Annu Rev Physiol 1989;51:67–80.
47.
Yang ML, Guh JY, Lai YH, Yang YL, Chang CC, Tsai JH, Chuang LY: Effects of high glucose on EGF effects and EGF receptors in the LLC-PK1 cells. Am J Nephrol 1997;17:193–198.
48.
Gilbert RE, Cox A, McNally PG, Wu LL, Dziadek M, Cooper ME, Jerums G: Increased epidermal growth factor in experimental diabetes related kidney growth in rats. Diabetologia 1997;40:778–785.
49.
Guh JY, Lai YH, Shin SJ, Chuang LY, Tsai JH: Epidermal growth factor in renal hypertrophy in streptozotocin-diabetic rats. Nephron 1991;59:641–647.
50.
Dagogo-Jack S, Marshall M, Kendall-Taylor P, Alberti KG: Urinary excretion of human epidermal growth factor in the various stages of diabetic nephropathy. Clin Endocrinol (Oxf) 1989;31:167–173.
51.
Mathiesen ER, Nexo E, Hommel E, Parving HH: Reduced urinary excretion of epidermal growth factor in incipient and overt diabetic nephropathy. Diabet Med 1989;6:121–126.
52.
Lee YJ, Shin SJ, Lin SR, Tan MS, Tsai JH: Increased expression of heparin binding epidermal growth-factor-like growth factor mRNA in the kidney of streptozotocin-induced diabetic rats. Biochem Biophys Res Commun 1995;207:216–222.
53.
Trachtman H, Koss I, Bogart M, Abramowitz J, Futterweit S, Franki N, Singhal PC: High glucose enhances growth factor-stimulated nitric oxide production by cultured rat mesangial cells. Res Commun Mol Pathol Pharmacol 1998;100:213–225.
54.
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.
55.
Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B, Casley DJ, Bach LA, Kelly DJ, Gilbert RE: Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 1999;48:2229–2239.
56.
Aiello LP, Wong JS: Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl 2000;77:113–119.
57.
Cha DR, Kim NH, Yoon JW, Jo SK, Cho WY, Kim HK, Won NH: Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl 2000;77:104–112.
58.
Kohan DE: Endothelins in the normal and diseased kidney. Am J Kidney Dis 1997;29:2–26.
59.
Badr KF, Murray JJ, Breyer MD, Takahashi K, Inagami T, Harris RC: Mesangial cell, glomerular and renal vascular responses to endothelin in the kidney. J Clin Invest 1989;83:336–342.
60.
Simonson MS, Wann S, Mene P, Dubyak GR, Kester M, Nakazato Y, Sedor JR, Dunn MJ: Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression and mitogenesis in rat mesangial cells. J Clin Invest 1989;83:702–712.
61.
Orisio S, Benigni A, Bruzzi I, Corna D, Perico N, Zoja C, Benatti L, Remuzzi G: Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression. Kidney Int 1993;43:354–358.
62.
Zoja C, Morigi M, Figliuzza M, Bruzzi, Oldroyd S, Benigni A, Ronco PM, Remuzzi G: Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins. Am J Kidney Dis 1995;26:934–941.
63.
Fukui M, Nakamura T, Ebihara I, Osada S, Tomino Y, Masaki T, Goto K, Furuichi Y, Koide H: Gene expression for endothelins and their receptors in glomeruli of diabetic rats. J Lab Clin Med 1993;122:126–127.
64.
Shin SJ, Lee YJ, Tsai JH: The correlation of plasma and urine endothelin-1 with the severity of nephropathy in Chinese patients with type 2 diabetes. Scand J Clin Lab Invest 1996;56:571–576.
65.
Hargrove GM, Dufresne J, Whiteside C, Muruve DA, Wong NCW: Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 2000;58:1534–1545.
66.
De Mattia G, Cassone Faldetta M, Bellini C, Bravi MC, Laurenti O, Baldoncini R, Santucci A, Ferri C: Role of plasma and urine endothelin-1 in early diabetic and hypertensive nephropathy. Am J Hypertens 1998;11:983–988.
67.
Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer H, Raschak M: Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 2001;87:161–169.
68.
Kelly DJ, Skinner SL, Gilbert RE, Cox AJ, Cooper ME, Wilkinson-Berka JL: Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat. Kidney Int 2000;57:1882–1994.
69.
Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, Brady HR: Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem 1999;274:5830–5834.
70.
Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, Goldschmeding R: Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 1998;53:853–861.
71.
Gupta S, Clarkson MR, Duggan J, Brady HR: Connective tissue growth factor: Potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int 2000;58:1389–1399.
72.
Dlugosz JA, Munk S, Ispanovic E, Goldberg HJ, Whiteside CI: Mesangial cell filamentous-actin disassembly and hypocontractility in high glucose are mediated by protein kinase C-etaX. Am J Physiol Renal Physiol 2001 Aug 15 [epub ahead of print].
73.
Murphy M, Clarkson M, Furlong F, Godson C, Martin F, Brady HR: Enhanced expression of cytoskeletal-related genes under hyperglycaemic conditions: Evidence that actin disassembly is independent of changes in TGF-β (abstract). J Am Soc Nephrol 2001;12:844.
74.
McMahon R, Murphy M, Clarkson M, Taal M, Mackenzie HS, Godson C, Martin F, Brady HR: IHG-2, a mesangial cell gene induced by high glucose, is human gremlin: Regulation by extracellular glucose concentration, cyclic mechanical mechanical strain, and transforming growth factor-beta1 J Biol Chem 2000;275:9901–9904.
75.
Zhang H, Wada J, Kanwar YS, Tsuchiyama Y, Hiragushi K, Hida K, Shikata K, Makino H: Screening for genes up-regulated in 5/6 nephrectomized mouse kidney. Kidney Int 1999;56:549–558.
76.
Holmes DI, Abdel Wahab N, Mason RM: Identification of glucosse-regulated genes in human mesangial cells by mRNA differential display. Biochem Biophys Res Commun 1997;238:179–184.
77.
Page R, Morris C, Williams J, von Ruhland C, Malik AN: Isolation of diabetes-associated kidney genes using differential display. Biochem Biophys Res Commun 1997;232:49–53.
78.
Wada J, Zhang H, Tsuchiyama Y, Hiragushi K, Hida K, Shikata K, Kanwar YS, Makino H: Gene expression profile in streptozotocin-induced diabetic mice kidneys undergoing glomerulosclerosis. Kidney Int 2001;59:1363–1373.
79.
Brownlee M: Advanced glycation end products in diabetic complications. Curr Opin Endocrinol Diabetes 1998;3:291–297.
80.
Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H: Advanced glycation end products in patients with diabetic nephropathy. N Engl J Med 1991;325:836–842.
81.
Nishino T, Horii Y, Shiiki H, Yamamoto H, Makita Z, Bucala R, Dohi K: Immunohistochemical detection of advanced glycation end products within the vascular lesions and glomeruli in diabetic nephropathy. Hum Pathol 1995;26:308–313.
82.
Makino H, Shikata K, Hironaka K, Kushiro M, Yamasaki Y, Sugimoto H, Ota S, Akari N, Horiuchi S: Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int 1995;48:517–526.
83.
Lee HB, Cha MK, Song KI, Kim JH, Lee EY, Kim SI, Kim J, Yoo MH: Pathogenic role of advanced glycosylation end products in diabetic nephropathy. Kidney Int Suppl 1997;60:60–65.
84.
Chen S, Cohen MP, Ziyadeh FN: Amadori-glycated albumin in diabetic nephropathy: Pathophysiologic connections. Kidney Int Suppl 2000;77:40–44.
85.
Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffer M: Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 1994;91:11704–11708.
86.
Yang CW, Vlassara H, Striker GE, Striker LJ: Administration of AGEs in vivo induces genes implicated in diabetic glomerulosclerosis. Kidney Int Suppl 1995;49:55–58.
87.
Yang CW, Vlassara H, Peten EP, He CJ, Striker GE, Striker LJ: Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA 1994;91:9436–9440.
88.
Schmidt AM, Hori O, Brett J, Yan S, Wautier JL, Stern D: Cellular receptors for advanced glycation end products: Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Atheroscler Thromb 1994;14:1521–1528.
89.
Salahudeen AK, Kanji V, Reckelhoff JF, Schmidt AM: Pathogenesis of diabetic nephropathy: A radical approach. Nephrol Dial Transplant 1997;12:664–668.
90.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–790.
91.
Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati V: Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 2001;11:1656–1666.
92.
Nishikawa T, Edelstein D, Brownlee M: The missing link: A single unifying mechanism for diabetic complications. Kidney Int Suppl 2000;77:26–30.
93.
Murphy M, McGinty A, Godson C: Protein kinases C: Potential targets for intervention in diabetic nephropathy. Curr Opin Nephrol Hypertens 1998;7:563–570.
94.
Lee TS, Saltsman KA, Ohashi H, King GL: Activation of protein kinase C by elevation of glucose concentration: Proposal for a mechanism in the development of diabetic microvascular complications. Proc Natl Acad Sci USA 1989;86:5141–5145.
95.
Craven PA, DeRubertis FR: Protein kinase C is activated in glomeruli from streptozotocin diabetic rats: Possible mediation by glucose. J Clin Invest 1989;83:1667–1675.
96.
Ayo SH, Radnik R, Garoni JA, Troyer DA, Kreisberg JI: High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Physiol 1991;261:F571–F577.
97.
Williams B, Schrier RW: Glucose-induced protein kinase C activity regulates arachidonic acid release and eicosanoid production by cultured glomerular mesangial cells. J Clin Invest 1993;92:2889–2896.
98.
Xia P, Kramer RM, King GL: Identification of the mechanism for the inhibition of Na+,K+-adenosine triphosphate by hyperglycaemia involving activation of protein kinase C and cytosolic PLA2. J Clin Invest 1995;96:733–740.
99.
Studer RK, Craven PA, DeRubertis FR: Activation of protein kinase C reduces thromboxane receptors in glomeruli and mesangial cells. Kidney Int 1993;44:58–64.
100.
Sharma K, Danoff TM, Depiero A, Ziyadeh FN: Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: Possible mediation via protein kinase C. Biochem Biophys Res Commun 1995;207:80–88.
101.
Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, Kikkawa R: Activation of mitogen-activated protein kinase cascade in diabetic glomeruli and mesangial cells cultured under high glucose conditions. Kidney Int Suppl 1997;60:66–69.
102.
Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL: Amelioration of vascular dysfunctions in diabetic rats by an oral PKCβ inhibitor. Science 1996;272:728–731.
103.
Koya D, Jirousek MR, Lin YW, Ishii H, Kuboki K, King GL: Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997;100:115–126.
104.
Dunlop M: Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl 2000;77:3–12.
105.
Heilig CW, Brosius FC 3rd, Henry DN: Glucose transporters of the glomerulus and the implications for diabetic nephropathy. Kidney Int Suppl 1997;60:91–99.
106.
Keogh RJ, Dunlop ME, Larkins RJ: The effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C and phospholipase A2 activation. Metabolism 1997;46:41–47.
107.
Rauscher FJ, Sambucetti LC, Curran T, Distel RJ, Spiegelman BM: Common DNA binding site for Fos protein complexes and transcription factor AP-1. Cell 1988;52:471–480.
108.
Rauscher FJ, Voulalas PJ, Franza BR, Curran T: Fos and Jun bind co-operatively to the AP-1 site: Reconstitution in vitro. Genes Dev 1988;2:1687–1699.
109.
Ingram AJ, Scholey JW: Protooncogene expression and diabetic kidney injury. Kidney Int Suppl 1997;60:70–76.
110.
Kreisberg JI, Kreisberg SH: High glucose activates protein kinase C and stimulates fibronectin gene expression by enhancing a cAMP responsive element. Kidney Int Suppl 1995;51:3–11.
111.
Ishida T, Haneda M, Maeda S, Koya D, Kikawa R: Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen activated protein kinase. Diabetes 1999;48:595–602.
112.
Weigert C, Sauer U, Brodbeck K, Pfeiffer A, Haring HU, Schleicher ED: AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-beta1 promoter in mesangial cells. J Am Soc Nephrol 2000;11:2007–2016.
113.
Ha H, Lee HB: Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int Suppl 2000;77:19–25.
114.
Goldberg HJ, Scholey J, Fantus IG: Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells. Diabetes 2000;49:863–871.
115.
Motojima M, Ando T, Yoshioka T: Sp1-like activity mediates angiotensin-II-induced plasminogen-activator inhibitor type-1 (PAI-1) gene expression in mesangial cells. Biochem J 2000;349:435–441.
116.
Wahab NA, Parker S, Sraer JD, Mason RM: The decorin high glucose response element and mechanism of its activation in human mesangial cells. J Am Soc Nephrol 2000;11:1607–1619.
117.
Lappin DWP, O’Seaghdha CM, Hannan K, Murphy M, Martin F, Godson C, Brady HR, Doran PP: Identification of a novel promoter fingerprint in high glucose cultured mesangial cell genes: Implication for the pathogenesis of diabetic nephropathy (abstract). J Am Soc Nephrol 2001;12:840.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.