• 1
    Doria A, Patti ME & Kahn CR (2008) The emerging genetic architecture of type 2 diabetes. Cell Metab 8, 186200.
  • 2
    Brosius FC 3rd, Alpers CE, Bottinger EP, Breyer MD, Coffman TM, Gurley SB, Harris RC, Kakoki M, Kretzler M, Leiter EH et al. (2009) Mouse models of diabetic nephropathy. J Am Soc Nephrol 20, 25032512.
  • 3
    Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M & Garcia-Perez J (2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 7, 327340.
  • 4
    Zong H, Ward M & Stitt AW (2011) AGEs, RAGE, and diabetic retinopathy. Curr Diab Rep 11, 244252.
  • 5
    Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, Pons DA, Owen RJ, Satchell SC, Miles MJ et al. (2010) Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 12, 329340.
  • 6
    Cheng Z, Tseng Y & White MF (2010) Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab 21, 589598.
  • 7
    Aguirre V, Uchida T, Yenush L, Davis R & White MF (2000) The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem 275, 90479054.
  • 8
    Carlson CJ, White MF & Rondinone CM (2004) Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. Biochem Biophys Res Commun 316, 533539.
  • 9
    Giraud J, Haas M, Feener EP, Copps KD, Dong X, Dunn SL & White MF (2007) Phosphorylation of Irs1 at SER-522 inhibits insulin signaling. Mol Endocrinol 21, 22942302.
  • 10
    Gual P, Gremeaux T, Gonzalez T, Le Marchand-Brustel Y & Tanti JF (2003) MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632. Diabetologia 46, 15321542.
  • 11
    Zick Y (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005, pe4.
  • 12
    Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C & White MF (2010) Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab 11, 8492.
  • 13
    Araki E, Lipes MA, Patti ME, Bruning JC, Haag B 3rd, Johnson RS & Kahn CR (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186190.
  • 14
    Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H, et al. (2000) Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia. Diabetes 49, 18801889.
  • 15
    Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S et al. (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182186.
  • 16
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI et al. (1998) Disruption of IRS2 causes type 2 diabetes in mice. Nature 391, 900904.
  • 17
    Zheng Y, Yamada H, Sakamoto K, Horita S, Kunimi M, Endo Y, Li Y, Tobe K, Terauchi Y, Kadowaki T et al. (2005) Roles of insulin receptor substrates in insulin-induced stimulation of renal proximal bicarbonate absorption. J Am Soc Nephrol 16, 22882295.
  • 18
    Carew RM, Sadagurski M, Goldschmeding R, Martin F, White MF & Brazil DP (2010) Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β? BMC Dev Biol 10, 73.
  • 19
    Mima A, Ohshiro Y, Kitada M, Matsumoto M, Geraldes P, Li C, Li Q, White GS, Cahill C, Rask-Madsen C et al. (2012) Glomerular-specific protein kinase Cβ-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. Kidney Int 79, 883896.
  • 20
    Thameem F, Puppala S, Schneider J, Bhandari B, Arya R, Arar NH, Vasylyeva TL, Farook VS, Fowler S, Almasy L et al. (2012) The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. Diabetes 61, 23852393.
  • 21
    Sivaskandarajah GA, Jeansson M, Maezawa Y, Eremina V, Baelde HJ & Quaggin SE (2012) Vegfa protects the glomerular microvasculature in diabetes. Diabetes 61, 29582966.
  • 22
    Veron D, Reidy KJ, Bertuccio C, Teichman J, Villegas G, Jimenez J, Shen W, Kopp JB, Thomas DB & Tufro A (2010) Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 77, 989999.
  • 23
    Veron D, Bertuccio CA, Marlier A, Reidy K, Garcia AM, Jimenez J, Velazquez H, Kashgarian M, Moeckel GW & Tufro A (2011) Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 54, 12271241.
  • 24
    Eremina V, Cui S, Gerber H, Ferrara N, Haigh J, Nagy A, Ema M, Rossant J, Jothy S, Miner JH et al. (2006) Vascular endothelial growth factor A signaling in the podocyte–endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 17, 724735.
  • 25
    Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH & Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111, 707716.
  • 26
    Sison K, Eremina V, Baelde H, Min W, Hirashima M, Fantus IG & Quaggin SE (2011) Glomerular structure and function require paracrine, not autocrine, VEGF–VEGFR-2 signaling. J Am Soc Nephrol 21, 16911701.
  • 27
    Manson SR, Niederhoff RA, Hruska KA & Austin PF (2011) The BMP7–Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. J Urol 185, 25232530.
  • 28
    Mitu GM, Wang S & Hirschberg R (2007) BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am J Physiol Renal Physiol 293, F1641F1648.
  • 29
    Sugimoto H, Grahovac G, Zeisberg M & Kalluri R (2007) Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes 56, 18251833.
  • 30
    Wang S, de Caestecker M, Kopp J, Mitu G, Lapage J & Hirschberg R (2006) Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol 17, 25042512.
  • 31
    Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA & Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285, F1060F1067.
  • 32
    Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F & Kalluri R (2003) BMP7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9, 964968.
  • 33
    Kazama I, Mahoney Z, Miner JH, Graf D, Economides AN & Kreidberg JA (2008) Podocyte-derived BMP7 is critical for nephron development. J Am Soc Nephrol 19, 21812191.
  • 34
    Grijelmo C, Rodrigue C, Svrcek M, Bruyneel E, Hendrix A, de Wever O & Gespach C (2007) Proinvasive activity of BMP7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. Cell Signal 19, 17221732.
  • 35
    Leeuwis JW, Nguyen TQ, Chuva de Sousa Lopes SM, Lopes SM, van der Giezen DM, van der Ven K, Rouw PJ, Offerhaus GJ, Mummery CL & Goldschmeding R (2011) Direct visualization of Smad1/5/8-mediated transcriptional activity identifies podocytes and collecting ducts as major targets of BMP signalling in healthy and diseased kidneys. J Pathol 224, 121132.
  • 36
    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I et al. (2011) A high-resolution anatomical atlas of the transcriptome in the mouse embryo. PLoS Biol 9, e1000582.
  • 37
    Uhlen M, Bjorling E, Agaton C, Szigyarto CA, Amini B, Andersen E, Andersson AC, Angelidou P, Asplund A, Asplund C et al. (2005) A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics 4, 19201932.
  • 38
    Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al. (2010) Towards a knowledge-based human protein atlas. Nat Biotechnol 28, 12481250.
  • 39
    Rafiqi FH, Zuber AM, Glover M, Richardson C, Fleming S, Jovanovic S, Jovanovic A, O'Shaughnessy KM & Alessi DR (2010) Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2, 6375.
  • 40
    Udelhoven M, Leeser U, Freude S, Hettich MM, Laudes M, Schnitker J, Krone W & Schubert M (2011) Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells. J Mol Endocrinol 44, 99113.
  • 41
    Carew RM, Browne MB, Hickey FB & Brazil DP (2011) IRS2 and FoxO3a signalling are involved in E-cadherin expression and TGF-β1-induced repression in kidney epithelial cells. FEBS J 278, 33703380.
  • 42
    Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ & White MF (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 7377.
  • 43
    Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A & White MF (2001) Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107, 181189.
  • 44
    Soiampornkul R, Tong L, Thangnipon W, Balazs R & Cotman CW (2008) Interleukin-1β interferes with signal transduction induced by neurotrophin-3 in cortical neurons. Brain Res 1188, 189197.
  • 45
    D'Alfonso R, Marini MA, Frittitta L, Sorge R, Frontoni S, Porzio O, Mariani LM, Lauro D, Gambardella S, Trischitta V et al. (2003) Polymorphisms of the insulin receptor substrate-2 in patients with type 2 diabetes. J Clin Endocrinol Metab 88, 317322.
  • 46
    Fantin VR, Lavan BE, Wang Q, Jenkins NA, Gilbert DJ, Copeland NG, Keller SR & Lienhard GE (1999) Cloning, tissue expression, and chromosomal location of the mouse insulin receptor substrate 4 gene. Endocrinology 140, 13291337.
  • 47
    Sun XJ, Pons S, Wang LM, Zhang Y, Yenush L, Burks D, Myers MG Jr, Glasheen E, Copeland NG, Jenkins NA et al. (1997) The IRS2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Mol Endocrinol 11, 251262.
  • 48
    Gibson SL, Ma Z & Shaw LM (2007) Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell Cycle 6, 631637.
  • 49
    Huang SS, Leal SM, Chen CL, Liu IH & Huang JS (2004) Cellular growth inhibition by TGF-β1 involves IRS proteins. FEBS Lett 565, 117121.
  • 50
    Senthil D, Choudhury GG, Abboud HE, Sonenberg N & Kasinath BS (2002) Regulation of protein synthesis by IGF-I in proximal tubular epithelial cells. Am J Physiol Renal Physiol 283, F1226F1236.
  • 51
    Nguyen TQ & Goldschmeding R (2008) Bone morphogenetic protein-7 and connective tissue growth factor: novel targets for treatment of renal fibrosis? Pharm Res 25, 24162426.
  • 52
    Walsh DW, Godson C, Brazil DP & Martin F (2010) Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol 20, 244256.
  • 53
    Zhang H, Schulz TJ, Espinoza DO, Huang TL, Emanuelli B, Kristiansen K & Tseng YH (2010) Cross talk between insulin and bone morphogenetic protein signaling systems in brown adipogenesis. Mol Cell Biol 30, 42244233.
  • 54
    Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L, Larsson C, Pedersen O & White MF (1998) Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes 47, 976979.
  • 55
    Kalidas K, Wasson J, Glaser B, Meyer JM, Duprat LJ, White MF & Permutt MA (1998) Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with type II diabetes: no evidence for a major susceptibility role. Diabetologia 41, 13891391.
  • 56
    Bottomley WE, Soos MA, Adams C, Guran T, Howlett TA, Mackie A, Miell J, Monson JP, Temple R, Tenenbaum-Rakover Y et al. (2009) IRS2 variants and syndromes of severe insulin resistance. Diabetologia 52, 12081211.
  • 57
    Pezzolesi MG, Poznik GD, Skupien J, Smiles AM, Mychaleckyj JC, Rich SS, Warram JH & Krolewski AS (2011) An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes. Kidney Int 80, 105111.
  • 58
    Wang SN, Lapage J & Hirschberg R (2001) Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol 12, 23922399.