The Use of Transgenic Animals in the Study of Diabetic Kidney Disease

L. Wogensen; S. Krag; Q. Chai; T. Ledet

doi:10.1055/s-2005-861365

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2005; 37: 17-25
DOI: 10.1055/s-2005-861365

Review

The Use of Transgenic Animals in the Study of Diabetic Kidney Disease

L. Wogensen¹ , S. Krag¹ , Q. Chai¹ , T. Ledet¹

¹ Research Laboratory of Biochemical Pathology, Aarhus University Hospital, 44 Nørrebrogade, Building 3B, 8000 Aarhus C, Denmark

Abstract

Diabetic nephropathy is one of the most common diseases leading to fibrosis and end-stage renal disease (ESRD) world wide. Under normal conditions, a delicate equilibrium exists between synthesis, composition, and removal of extracellular matrix (ECM). If this is disturbed, ECM accumulation and fibrosis may result. The fragile balance between synthesis and removal of ECM is crucial for the prognosis of glomerular as well as interstitial pathological processes. Some features may favor ECM accumulation and progression to ESRD (dialysis and transplantation), whereas other elements may favor ECM removal and resolution (recovery). Pathogenetic mechanisms and the cellular sources of ECM in the glomerular basement membrane as well as in the tubulointerstitial space are still under investigation. Among several growth factors, transforming growth factor β1 (TGF-β1) plays a major role. We consider the use of living animals necessary for our understanding of the complex biological processes that occur during the development of ESRD. The present review will discuss the glomerular as well as interstitial accumulation of ECM and the use of transgenic animals in studying the pathogenetic mechanisms with special emphasis on diabetic kidney disease and TGF-β1.

Key words

Transforming growth factor β1 - Extracellular matrix - Diabetes - Transgenic models

Full Text

References

1 Borch Johnsen K. The prognosis of insulin-dependent diabetes mellitus. An epidemiological approach. Dan Med Bull. 1989; 36 336-348
2 Andresen J L, Rasmussen L M, Ledet T. Diabetic macroangiopathy and atherosclerosis. Diabetes. 1996; 45 Suppl 3 S91-S94
3 Rasmussen L M, Heickendorff L. Accumulation of fibronectin in aortas from diabetic patients. A quantitative immunohistochemical and biochemical study. Lab Invest. 1989; 61 440-446
4 Rasmussen L M, Ledet T. Aortic collagen alterations in human diabetes mellitus. Changes in basement membrane collagen content and in the susceptibility of total collagen to cyanogen bromide solubilisation. Diabetologia. 1993; 36 445-453
5 Heickendorff L, Ledet T, Rasmussen L M. Glycosaminoglycans in the human aorta in diabetes mellitus: a study of tunica media from areas with and without atherosclerotic plaque. Diabetologia. 1994; 37 286-292
6 Bunn H F. Nonenzymatic glycosylation of protein: relevance to diabetes. Am J Med. 1981; 70 325-330
7 Flyvbjerg A. The Role of Insulin-like Growth Factor I in Initial Renal Hypertrophy in Experimental Diabetes. 1993. Aarhus University. Ref Type: Thesis/Dissertation.
8 Suzuki D, Yagame M, Kim Y, Sakai H, Mauer M. Renal in situ hybridization studies of extracellular matrix related molecules in type 1 diabetes mellitus. Nephron. 2002; 92 564-572
9 Abrass C K, Spicer D, Berfield A K, St John P L, Abrahamson D R. Diabetes induces changes in glomerular development and laminin-beta 2 (s-laminin) expression. Am J Pathol. 1997; 151 1131-1140
10 Nerlich A, Schleicher E. Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol. 1991; 139 889-899
11 Yang C W, Vlassara H, Peten E P, He C J, Striker G E, Striker L J. Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci U S A. 1994; 91 9436-9440
12 Doi T, Vlassara H, Kirstein M, Yamada Y, Striker G E, Striker L J. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992; 89 2873-2877
13 Sinniah R, Khan T N. Renal tubular basement membrane changes in tubulointerstitial damage in patients with glomerular diseases. Ultrastruct Pathol. 1999; 23 359-368
14 Eddy A A. Molecular basis of renal fibrosis. Pediatr Nephrol. 2000; 15 290-301
15 Norman J T, Fine L G. Progressive renal disease: fibroblasts, extracellular matrix, and integrins. Exp Nephrol. 1999; 7 167-177
16 Iwano M, Neilson E G. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 2004; 13 279-284
17 Bader R, Bader H, Grund K E, Mackensen-Haen S, Christ H, Bohle A. Structure and function of the kidney in diabetic glomerulosclerosis. Correlations between morphological and functional parameters. Pathol Res Pract. 1980; 167 204-216
18 Schainuck L I, Striker G E, Cutler R E, Benditt E P. Structural-functional correlations in renal disease. II. The correlations. Hum Pathol. 1970; 1 631-641
19 Striker G E, Schainuck L I, Cutler R E, Benditt E P. Structural-functional correlations in renal disease. I. A method for assaying and classifying histopathologic changes in renal disease. Hum Pathol. 1970; 1 615-630
20 Ha T S, Barnes J L, Stewart J L, Ko C W, Miner J H, Abrahamson D R, Sanes J R, Kasinath B S. Regulation of renal laminin in mice with type II diabetes. J Am Soc Nephrol. 1999; 10 1931-1939
21 Miner J H. Developmental biology of glomerular basement membrane components. Curr Opin Nephrol Hypertens. 1998; 7 13-19
22 Miner J H. Renal basement membrane components. Kidney Int. 1999; 56 2016-2024
23 Bruijn J A, Roos A, de Geus B, de Heer E. Transforming growth factor-beta and the glomerular extracellular matrix in renal pathology. J Lab Clin Med. 1994; 123 34-47
24 Brees D K, Hutchison F N, Cole G J, Williams J C. Differential effects of diabetes and glomerulonephritis on glomerular basement membrane composition. Proc Soc Exp Biol Med. 1996; 212 69-77
25 Fogo A B. Mesangial matrix modulation and glomerulosclerosis. Exp Nephrol. 1999; 7 147-159
26 Schnaper H W, Kopp J B. Renal fibrosis. Front Biosci. 2003; 8 e68-e86
27 Bergijk E C, Van Alderwegen I E, Baelde H J, de Heer E, Funabiki K, Miyai H, Killen P D, Kalluri R K, Bruijn J A. Differential expression of collagen IV isoforms in experimental glomerulosclerosis. J Pathol. 1998; 184 307-315
28 Muchaneta-Kubara E C, el Nahas A M. Myofibroblast phenotypes expression in experimental renal scarring. Nephrol Dial Transplant. 1997; 12 904-915
29 Strutz F, Zeisberg M, Ziyadeh F N, Yang C Q, Kalluri R, Muller G A, Neilson E G. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002; 61 1714-1728
30 Okada H, Inoue T, Suzuki H, Strutz F, Neilson E G. Epithelial-mesenchymal transformation of renal tubular epithelial cells in vitro and in vivo. . Nephrol Dial Transplant. 2000; 15 Suppl 6 44-46
31 Okada H, Danoff T M, Kalluri R, Neilson E G. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 1997; 273 F563-F574
32 Strutz F, Muller G A, Neilson E G. Transdifferentiation: a new angle on renal fibrosis. Exp Nephrol. 1996; 4 267-270
33 Zeisberg M, Bonner G, Maeshima Y, Colorado P, Muller G A, Strutz F, Kalluri R. Renal Fibrosis. Collagen Composition and Assembly Regulates Epithelial-Mesenchymal Transdifferentiation. Am J Pathol. 2001; 159 1313-1321
34 Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001; 159 1465-1475
35 Stahl P J, Felsen D. Transforming growth factor-beta, basement membrane, and epithelial-mesenchymal transdifferentiation: implications for fibrosis in kidney disease. Am J Pathol. 2001; 159 1187-1192
36 Fan J M, Ng Y Y, Hill P A, Nikolic-Paterson D J, Mu W, Atkins R C, Lan H Y. Transforming growth factor-beta regulates tubular epithelial- myofibroblast transdifferentiation in vitro. Kidney Int. 1999; 56 1455-1467
37 Fan J M, Huang X R, Ng Y Y, Nikolic-Paterson D J, Mu W, Atkins R C, Lan H Y. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. Am J Kidney Dis. 2001; 37 820-831
38 Rastaldi M P, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, Strutz F, Muller G A, Colasanti G, D’Amico G. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int. 2002; 62 137-146
39 Lavaud S, Poirier B, Mandet C, Belair M F, Irinopoulou T, Heudes D, Bazin R, Bariety J, Myara I, Chevalier J. Inflammation is probably not a prerequisite for renal interstitial fibrosis in normoglycemic obese rats. Am J Physiol Renal Physiol. 2001; 280 F683-F694
40 Oba S, Kimura K, Suzuki N, Mise N, Tojo A, Miyashita K, Konno Y, Hirata Y, Goto A, Omata M. Relevance of periglomerular myofibroblasts in progression of human glomerulonephritis. Am J Kidney Dis. 1998; 32 419-425
41 Meyer T W, Anderson S, Rennke H G, Brenner B M. Reversing glomerular hypertension stabilizes established glomerular injury. Kidney Int. 1987; 31 752-759
42 Anderson S, Meyer T W, Rennke H G, Brenner B M. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1985; 76 612-619
43 Riser B L, Cortes P, Yee J. Modelling the effects of vascular stress in mesangial cells. Curr Opin Nephrol Hypertens. 2000; 9 43-47
44 Riser B L, Cortes P, Heilig C, Grondin J, Ladson-Wofford S, Patterson D, Narins R G. Cyclic stretching force selectively up-regulates transforming growth factor-beta isoforms in cultured rat mesangial cells. Am J Pathol. 1996; 148 1915-1923
45 Shimamura T, Morrison A B. A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol. 1975; 79 95-106
46 Fine L G, Orphanides C, Norman J T. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl. 1998; 65 S74-S78
47 Schrijvers B F, De Vriese A S, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004; 25 971-1010
48 Wang S N, LaPage J, Hirschberg R. Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome. Kidney Int. 1999; 56 1247-1251
49 Wang S N, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int. 2000; 57 1002-1014
50 Creely J J, DiMari S J, Howe A M, Haralson M A. Effects of transforming growth factor-beta on collagen synthesis by normal rat kidney epithelial cells. Am J Pathol. 1992; 140 45-55
51 Daniel C, Wiede J, Krutzsch H C, Ribeiro S M, Roberts D D, Murphy-Ullrich J E, Hugo C. Thrombospondin-1 is a major activator of TGF-beta in fibrotic renal disease in the rat in vivo. Kidney Int. 2004; 65 459-468
52 Ziyadeh F N, Sharma K, Ericksen M, Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest. 1994; 93 536-542
53 Nakamura T, Miller D, Ruoslahti E, Border W A. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int. 1992; 41 1213-1221
54 Overall C M, Wrana J L, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem. 1989; 264 1860-1869
55 Hill C, Flyvbjerg A, Gronbaek H, Petrik J, Hill D J, Thomas C R, Sheppard M C, Logan A. The renal expression of transforming growth factor-beta isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology. 2000; 141 1196-1208
56 Singh R, Song R H, Alavi N, Pegoraro A A, Singh A K, Leehey D J. High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1. Exp Nephrol. 2001; 9 249-257
57 Yamamoto T, Noble N A, Cohen A H, Nast C C, Hishida A, Gold L I, Border W A. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 1996; 49 461-469
58 Iwano M, Kubo A, Nishino T, Sato H, Nishioka H, Akai Y, Kurioka H, Fujii Y, Kanauchi M, Shiiki H, Dohi K. Quantification of glomerular TGF-b1 mRNA in patients with diabetes mellitus. Kidney Int. 1996; 49 1120-1126
59 Sharma K, Ziyadeh F N, Alzahab B, McGowan T A, Kapoor S, Kurnik B RC, Kurnik P B, Weisberg L S. Increased Renal Production of Transforming Growth Factor-b1 in Patients with Type II Diabetes. Diabetes. 1997; 46 854-859
60 Shankland S J, Scholey J W, Ly H, Thai K. Expression of transforming growth factor-beta 1 during diabetic renal hypertrophy. Kidney Int. 1994; 46 430-442
61 Sharma K, Ziyadeh F N. Renal hypertrophy is associated with upregulation of TGF-beta 1 gene expression in diabetic BB rat and NOD mouse. Am J Physiol. 1994; 267 F1094-01
62 Olsen T S, Orskov H, Lundbaek K. Kidney lesions in rats with severe long-term alloxan diabetes. 2. Histochemical studies, comparison with human diabetic glomerular lesions. Acta Pathol Microbiol Scand. 1966; 66 1-12
63 Yang C W, Hattori M, Vlassara H, He C J, Carome M A, Yamato E, Elliot S, Striker G E, Striker L J. Overexpression of transforming growth factor-beta 1 mRNA is associated with up-regulation of glomerular tenascin and laminin gene expression in nonobese diabetic mice. J Am Soc Nephrol. 1995; 5 1610-1617
64 Yamamoto T, Nakamura T, Noble N A, Ruoslahti E, Border W A. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993; 90 1814-1818
65 Bódi I, Kimmel P L, Abraham A A, Svetkey L P, Klotman P E, Kopp J B. Renal TGF-beta in HIV-associated kidney diseases. Kidney Int. 1997; 51 1568-1577
66 Yoshioka K, Takemura T, Murakami K, Okada M, Hino S, Miyamoto H, Maki S. Transforming growth factor-beta protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest. 1993; 68 154-163
67 Border W A, Yamamoto T, Noble N A. Transforming growth factor beta in diabetic nephropathy. Diabetes Metab Rev. 1996; 12 309-339
68 Niemir Z I, Stein H, Noronha I L, Krüger C, Andrassy K, Ritz E, Waldherr R. PDGF and TGF-beta contribute to the natural course of human IgA glomerulonephritis. Kidney Int. 1995; 48 1530-1541
69 Coimbra T, Wiggins R, Noh J W, Merritt S, Phan S H. Transforming growth factor-beta production in anti-glomerular basement membrane disease in the rabbit. Am J Pathol. 1991; 138 223-234
70 Yamamoto T, Noble N A, Miller D E, Border W A. Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis. Kidney Int. 1994; 45 916-927
71 Border W A, Noble N A. TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int. 1997; 51 1388-1396
72 Border W A, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest. 1992; 90 1-7
73 Wogensen L, Nielsen C B, Hjorth P, Rasmussen L M, Høj Nielsen A, Gross K, Sarvetnick N, Ledet T. Under control of the Renin-1c promoter, Locally, produced transforming growth factor-b1 induces accumulation of glomerular extracellular matrix in transgenic mice. Diabetes. 1999; 48 182-192
74 Liu Y. Hepatocyte growth factor and the kidney. Curr Opin Nephrol Hypertens. 2002; 11 23-30
75 Mizuno S, Nakamura T. Suppressions of chronic glomerular injuries and TGF-beta 1 production by HGF in attenuation of murine diabetic nephropathy. Am J Physiol Renal Physiol. 2004; 286 F134-F143
76 Cruzado J M, Lloberas N, Torras J, Riera M, Fillat C, Herrero-Fresneda I, Aran J M, Alperovich G, Vidal A, Grinyo J M. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes. 2004; 53 1119-1127
77 Doi T, Striker L J, Quaife C, Conti F G, Palmiter R, Behringer R, Brinster R, Striker G E. Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulinlike growth factor-1. Am J Pathol. 1988; 131 398-403
78 Doi T, Striker L J, Gibson C C, Agodoa L Y, Brinster R L, Striker G E. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol. 1990; 137 541-552
79 Doi T, Striker L J, Kimata K, Peten E P, Yamada Y, Striker G E. Glomerulosclerosis in mice transgenic for growth hormone. Increased mesangial extracellular matrix is correlated with kidney mRNA levels. J Exp Med. 1991; 173 1287-1290
80 Kopp J B, Factor V M, Mozes M, Nagy P, Sanderson N, Bottinger E P, Klotman P E, Thorgeirsson S S. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest. 1996; 74 991-1003
81 Clouthier D E, Comerford S A, Hammer R E. Hepatic Fibrosis, Glomerulosclerosis, and a Lipodystrophy-like Syndrome in PEPCK-TGF-b1 Transgenic mice. J Clin Invest. 1997; 100 2697-2713
82 Kopp J B. Glomerulosclerosis, tubulointerstitial fibrosis, and obstructive uropathy in PEPCK-TGF-beta1 transgenic mice. Am J Kidney Dis. 1999; 34 177-183
83 Krag S, Østerby R, Chai Q, Nielsen B, Hermans C, Wogensen L. TGF-b1-induced glomerular disorder is associated with impaired concentrating ability mimicking primary glomerular disease with renal failure in man. Lab Invest. 2000; 80 1855-1868
84 Østerby R. Lesions from kidney biopsies. Diabetes Metab Rev. 1996; 12 151-174
85 Chai Q, Krag S, Miner J H, Nyengaard J R, Chai S, Wogensen L. TGF-beta1 induces aberrant laminin chain and collagen type IV isotype expression in the glomerular basement membrane. Nephron Exp Nephrol. 2003; 94 e123-e136
86 Birch N C, Krag S, Osterby R, Flyvbjerg A, Nyengaard J, Forman A, Wogensen L. Transforming growth factor beta1-induced glomerulopathy is prevented by 17beta-estradiol supplementation. Virchows Arch. 2004; 444 561-566
87 Chai Q, Krag S, Chai S, Ledet T, Wogensen L. Localisation and phenotypical characterisation of collagen-producing cells in TGF-beta 1-induced renal interstitial fibrosis. Histochem Cell Biol. 2003; 119 267-280
88 Cosgrove D, Rodgers K D, Meehan D T, Miller C C, Bovard K, Gilroy A, Gardner H, Koteliansky V, Gotwals P, Amatucci A, Kalluri R. Integrin a1b1 and Transforming growth factor-b1 play distinct roles in Alport glomerular pathogenesis and serve dual targets for metabolic therapy. Am J Pathol. 2000; 157 1649-1659
89 Kashtan C E, Kim Y, Lees G E, Thorner P S, Virtanen I, Miner J H. Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: aberrant laminin alpha2 deposition is species independent. J Am Soc Nephrol. 2001; 12 252-260
90 Takeuchi A, Yoshizawa N, Yamamoto M, Sawasaki Y, Oda T, Senoo A, Niwa H, Fuse Y. Basic fibroblast growth factor promotes proliferation of rat glomerular visceral epithelial cells in vitro. Am J Pathol. 1992; 141 107-116
91 van Det N F, Verhagen N AM, Tamsma J T, Berden J HM, Bruijn J A, Daha M R, van der Woude F J. Regulation of Glomerular Epithelial Cell Production of Fibronectin and Transforming Growth Factor-b by High Glucose, Not by Angiotensin II. Diabetes. 1997; 46 834-840
92 Neubauer K, Kruger M, Quondamatteo F, Knittel T, Saile B, Ramadori G. Transforming growth factor-beta1 stimulates the synthesis of basement membrane proteins laminin, collagen type IV and entactin in rat liver sinusoidal endothelial cells. J Hepatol. 1999; 31 692-702
93 MacKay K, Striker L J, Stauffer J W, Doi T, Agodoa L Y, Striker G E. Transforming growth factor-beta. Murine glomerular receptors and responses of isolated glomerular cells. J Clin Invest. 1989; 83 1160-1167
94 Bertelli R, Valenti F, Oleggini R, Caridi G, Altieri P, Coviello D A, Botti G, Ravazzolo R, Ghiggeri G M. Cell-specific regulation of alpha1(III) and alpha2(V) collagen by TGF-beta1 in tubulointerstitial cell models. Nephrol Dial Transplant. 1998; 13 573-579
95 Han D C, Isono M, Hoffman B B, Ziyadeh F N. High glucose stimulates proliferation and collagen type I synthesis in renal cortical fibroblasts: mediation by autocrine activation of TGF-beta. J Am Soc Nephrol. 1999; 10 1891-1899
96 Le Meur Y, Tesch G H, Rice E, Foti R, Atkins R C, Paterson D JN. Blockade of macrophage accumulation has no effect on renal fibrosis in obstructive nephropathy. Ref Type: Abstract. J Am Soc Nephrol. 2001; 12 708A
97 Shankland S J, Johnson R J. TGF-beta in glomerular disease. Miner Electrolyte Metab. 1998; 24 168-173

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