Role of upstream stimulatory factor 2 in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). About 20%–30% of people with type 1 and type 2 diabetes develop DN . DN is characterized by both glomerulosclerosis with thickening of the glomerular basement membrane and mesangial matrix expansion, and tubulointerstitial fibrosis . Hyperglycemia and the activation of the intra-renal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of DN. However, the mechanisms are not well known.

Studies from our laboratory demonstrated that the transcription factor—upstream stimulatory factor 2 (USF2) is an important regulator of DN. Moreover, the renin gene is a downstream target of USF2. Importantly, USF2 transgenic (Tg) mice demonstrate a specific increase in renal renin expression and angiotensin II (AngII) levels in kidney and exhibit increased urinary albumin excretion and extracellular matrix deposition in glomeruli, supporting a role for USF2 in the development of diabetic nephropathy. In this review, we summarize our findings of the mechanisms by which diabetes regulates USF2 in kidney cells and its role in regulation of renal renin-angiotensin system and the development of diabetic nephropathy.

Keywords

USF2 / renin-angiotensin system / TGF-β / renal fibrosis

References

1	Andersen S, Tarnow L, Rossing P, Hansen B V, Parving H H (2000). Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int, 57(2): 601-606
2	Anderson S, Jung F F, Ingelfinger J R (1993). Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol, 265(4 Pt 2): F477-F486
3	Andrade A Q, Casarini D E, Schor N, Boim M A (2002). Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells. Braz J Med Biol Res, 35(1): 17-24
4	Bertoluci M C, Schmid H, Lachat J J, Coimbra T M (1996). Transforming growth factor-beta in the development of rat diabetic nephropathy. A 10-month study with insulin-treated rats. Nephron, 74(1): 189-196
5	Bidder M, Shao J S, Charlton-Kachigian N, Loewy A P, Semenkovich C F, Towler D A (2002). Osteopontin transcription in aortic vascular smooth muscle cells is controlled by glucose-regulated upstream stimulatory factor and activator protein-1 activities. J Biol Chem, 277(46): 44485-44496
6	Borch-Johnsen K, Andersen P K, Deckert T (1985). The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia, 28(8): 590-596
7	Border W A, Noble N A (1998a). Evidence that TGF-beta should be a therapeutic target in diabetic nephropathy. Kidney Int, 54(4): 1390-1391
8	Border W A, Noble N A (1998b). Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension, 31(1 Pt 2): 181-188
9	Border W A, Noble N A, Ketteler M (1995). TGF-beta: a cytokine mediator of glomerulosclerosis and a target for therapeutic intervention. Kidney Int Suppl, 49(61): S59-S61
10	Brenner B M, Cooper M E, de Zeeuw D, Keane W F, Mitch W E, Parving H H, Remuzzi G, Snapinn S M, Zhang Z, Shahinfar S, and the RENAAL Study Investigators (2001). Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 345(12): 861-869
11	Burden A C, Thurston H (1979). Plasma renin activity in diabetes mellitus. Clin Sci (Lond), 56(3): 255-259
12	Carey R M, Siragy H M (2003). The intrarenal renin-angiotensin system and diabetic nephropathy. Trends Endocrinol Metab, 14(6): 274-281
13	Chan J C, Ko G T, Leung D H, Cheung R C, Cheung M Y, So W Y, Swaminathan R, Nicholls M G, Critchley J A, Cockram C S (2000). Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Kidney Int, 57(2): 590-600
14	Chen L, Shen Y H, Wang X, Wang J, Gan Y, Chen N, Wang J, LeMaire S A, Coselli J S, Wang X L (2006). Human prolyl-4-hydroxylase alpha(I) transcription is mediated by upstream stimulatory factors. J Biol Chem, 281(16): 10849-10855
15	Chen S, Hong S W, Iglesias-de la Cruz M C, Isono M, Casaretto A, Ziyadeh F N (2001). The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. Ren Fail, 23(3-4): 471-481
16	Cooper M E (2001). Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia, 44(11): 1957-1972
17	Corre S, Galibert M D (2005). Upstream stimulating factors: highly versatile stress-responsive transcription factors. Pigment Cell Res, 18(5): 337-348
18	Dabhi B, Mistry K N (2015). Oxidative stress and its association with TNF-alpha-308 G/C and IL-1alpha-889 C/T gene polymorphisms in patients with diabetes and diabetic nephropathy. Gene. 56(2): 197-202
19	Daniel C, Schaub K, Amann K, Lawler J, Hugo C (2007). Thrombospondin-1 is an endogenous activator of TGF-beta in experimental diabetic nephropathy in vivo. Diabetes, 56(12): 2982-2989
20	Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart R E, Acton S (2000). A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res, 87(5): E1-E9
21	Durvasula R V, Shankland S J (2008). Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol, 294(4): F830-F839
22	Erman A, Veksler S, Gafter U, Boner G, Wittenberg C, van Dijk D J (2004). Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat. J Renin Angiotensin Aldosterone Syst, 5(3): 146-151
23	Feener E P, King G L (1997). Vascular dysfunction in diabetes mellitus. Lancet, 350(Suppl 1): SI9-SI13
24	Feldman D L, Jin L, Xuan H, Contrepas A, Zhou Y, Webb R L, Mueller D N, Feldt S, Cumin F, Maniara W, Persohn E, Schuetz H, Jan Danser A H, Nguyen G (2008). Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension, 52(1): 130-136
25	Ferrario C M, Trask A J, Jessup J A (2005). Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol, 289(6): H2281-H2290
26	Fogo A B (1999). Mesangial matrix modulation and glomerulosclerosis. Exp Nephrol, 7(2): 147-159
27	Forbes J M, Fukami K, Cooper M E (2007). Diabetic nephropathy: where hemodynamics meets metabolism. Exp Clin Endocrinol Diabetes, 115(2): 69-84
28	Giacco F, Brownlee M (2010). Oxidative stress and diabetic complications. Circ Res, 107(9): 1058-1070
29	Gleizes P E, Munger J S, Nunes I, Harpel J G, Mazzieri R, Noguera I, Rifkin D B (1997). TGF-beta latency: biological significance and mechanisms of activation. Stem Cells, 15(3): 190-197
30	Gurley S B, Coffman T M (2007). The renin-angiotensin system and diabetic nephropathy. Semin Nephrol, 27(2): 144-152
31	Hadsell D L, Bonnette S, George J, Torres D, Klimentidis Y, Gao S, Haney P M, Summy-Long J, Soloff M S, Parlow A F, Sirito M, Sawadogo M (2003). Diminished milk synthesis in upstream stimulatory factor 2 null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors 4E and 4G. Mol Endocrinol, 17(11): 2251-2267
32	Hong S W, Isono M, Chen S, Iglesias-De La Cruz M C, Han D C, Ziyadeh F N (2001). Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. Am J Pathol, 158(5): 1653-1663
33	Hsieh T J, Fustier P, Zhang S L, Filep J G, Tang S S, Ingelfinger J R, Fantus I G, Hamet P, Chan J S (2003). High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells. Endocrinology, 144(10): 4338-4349
34	Ichihara A, Suzuki F, Nakagawa T, Kaneshiro Y, Takemitsu T, Sakoda M, Nabi A H, Nishiyama A, Sugaya T, Hayashi M, Inagami T (2006). Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol, 17(7): 1950-1961
35	Ishimura E, Sterzel R B, Morii H, Kashgarian M (1992). Extracellular matrix protein: gene expression and synthesis in cultured rat mesangial cells. Nihon Jinzo Gakkai Shi, 34(1): 9-17
36	Isono M, Chen S, Hong S W, Iglesias-de la Cruz M C, Ziyadeh F N (2002). Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells. Biochem Biophys Res Commun, 296(5): 1356-1365
37	Kagami S, Border W A, Miller D E, Noble N A (1994). Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest, 93(6): 2431-2437
38	Kanwar Y S, Wada J, Sun L, Xie P, Wallner E I, Chen S, Chugh S, Danesh F R (2008). Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood), 233(1): 4-11
39	Kelly D J, Zhang Y, Moe G, Naik G, Gilbert R E (2007). Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia, 50(11): 2398-2404
40	Kingsley-Kallesen M, Luster T A, Rizzino A (2001). Transcriptional regulation of the transforming growth factor-beta2 gene in glioblastoma cells. In Vitro Cell Dev Biol Anim, 37(10): 684-690
41	Kobori H, Nangaku M, Navar L G, Nishiyama A (2007). The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev, 59(3): 251-287
42	Lawrence D A (1996). Transforming growth factor-beta: a general review. Eur Cytokine Netw, 7(3): 363-374
43	Leehey D J, Singh A K, Alavi N, Singh R (2000). Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl, 77(8): S93-S98
44	Leehey D J, Singh A K, Bast J P, Sethupathi P, Singh R (2008). Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. Transl Res, 151(4): 208-216
45	Lewis E J (2002). The role of angiotensin II receptor blockers in preventing the progression of renal disease in patients with type 2 diabetes. Am J Hypertens, 15(10 Pt 2): 123S-128S
46	Lewis E J, Hunsicker L G, Clarke W R, Berl T, Pohl M A, Lewis J B, Ritz E, Atkins R C, Rohde R, Raz I, and the Collaborative Study Group (2001). Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med, 345(12): 851-860
47	Li Y, Wang S (2010). Glycated albumin upregulates upstream stimulatory factor 2 gene transcription in mesangial cells. Am J Physiol Renal Physiol, 299(1): F121-F127
48	Lim A Kh (2014). Diabetic nephropathy- complications and treatment. Int J Nephrol Renovasc Dis, 7: 361-381
49	Liu F, Brezniceanu M L, Wei C C, Chénier I, Sachetelli S, Zhang S L, Filep J G, Ingelfinger J R, Chan J S (2008). Overexpression of angiotensinogen increases tubular apoptosis in diabetes. J Am Soc Nephrol, 19(2): 269-280
50	Liu S, Shi L, Wang S (2007). Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury. Am J Physiol Renal Physiol, 293(5): F1727-F1735
51	Lyons R M, Gentry L E, Purchio A F, Moses H L (1990). Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol, 110(4): 1361-1367
52	Márquez E, Riera M, Pascual J, Soler M J (2015). Renin-angiotensin system within the diabetic podocyte. Am J Physiol Renal Physiol, 308(1): F1-F10
53	Miyata N, Park F, Li X F, Cowley A W Jr (1999). Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am J Physiol, 277(3 Pt 2): F437-F446
54	Navar L G, Harrison-Bernard L M, Nishiyama A, Kobori H (2002). Regulation of intrarenal angiotensin II in hypertension. Hypertension, 39(2 Pt 2): 316-322
55	Navar L G, Inscho E W, Majid S A, Imig J D, Harrison-Bernard L M, Mitchell K D (1996). Paracrine regulation of the renal microcirculation. Physiol Rev, 76(2): 425-536
56	Navarro-González J F, Mora-Fernández C (2008). The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol, 19(3): 433-442
57	Nguyen G, Bouzhir L, Delarue F, Rondeau E, Sraer J D (1998). [Evidence of a renin receptor on human mesangial cells: effects on PAI1 and cGMP]. Nephrologie, 19(7): 411-416 (Evidence of a renin receptor on human mesangial cells: effects on PAI1 and cGMP)
58	Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer J D (1996). Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int, 50(6): 1897-1903
59	Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001). Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA, 98(15): 8780-8785
60	Niranjan T, Bielesz B, Gruenwald A, Ponda M P, Kopp J B, Thomas D B, Susztak K (2008). The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med, 14(3): 290-298
61	Oh J H, Ha H, Yu M R, Lee H B (1998). Sequential effects of high glucose on mesangial cell transforming growth factor-beta 1 and fibronectin synthesis. Kidney Int, 54(6): 1872-1878
62	Pan L, Black T A, Shi Q, Jones C A, Petrovic N, Loudon J, Kane C, Sigmund C D, Gross K W (2001). Critical roles of a cyclic AMP responsive element and an E-box in regulation of mouse renin gene expression. J Biol Chem, 276(49): 45530-45538
63	Park J T, Kato M, Lanting L, Castro N, Nam B Y, Wang M, Kang S W, Natarajan R (2014). Repression of let-7 by transforming growth factor-β1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions. Am J Physiol Renal Physiol, 307(12): F1390-F1403
64	Parving H H, Persson F, Lewis J B, Lewis E J, Hollenberg N K, the AVOID Study Investigators (2008). Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med, 358(23): 2433-2446
65	Peach M J (1977). Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev, 57(2): 313-370
66	Petrica L, Vlad A, Gluhovschi G, Gadalean F, Dumitrascu V, Vlad D, Popescu R, Velciov S, Gluhovschi C, Bob F, Ursoniu S, Petrica M, Jianu D C (2015). Glycated peptides are associated with the variability of endothelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study. J Diabetes Complications, 29(2): 230-237
67	Phillips A (2007). The role of proximal tubular cells in interstitial fibrosis: understanding TGF-beta1. Chang Gung Med J, 30(1): 2-6
68	Phillips A, Janssen U, Floege J (1999). Progression of diabetic nephropathy. Insights from cell culture studies and animal models. Kidney Blood Press Res, 22(1-2): 81-97
69	Price D A, Porter L E, Gordon M, Fisher N D, De’Oliveira J M, Laffel L M, Passan D R, Williams G H, Hollenberg N K (1999). The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol, 10(11): 2382-2391
70	Qian J, Kaytor E N, Towle H C, Olson L K (1999). Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic beta-cells. Biochem J, 341 (Pt 2): 315-322
71	Qyang Y, Luo X, Lu T, Ismail P M, Krylov D, Vinson C, Sawadogo M (1999). Cell-type-dependent activity of the ubiquitous transcription factor USF in cellular proliferation and transcriptional activation. Mol Cell Biol, 19(2): 1508-1517
72	Re R (2007). Intracellular renin-angiotensin system: the tip of the intracrine physiology iceberg. Am J Physiol Heart Circ Physiol, 293(2): H905-H906
73	Riccio A, Pedone P V, Lund L R, Olesen T, Olsen H S, Andreasen P A (1992). Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. Mol Cell Biol, 12(4): 1846-1855
74	Rifkin D B, Kojima S, Abe M, Harpel J G (1993). TGF-beta: structure, function, and formation. Thromb Haemost, 70(1): 177-179
75	Rippe R A, Umezawa A, Kimball J P, Breindl M, Brenner D A (1997). Binding of upstream stimulatory factor to an E-box in the 3′-flanking region stimulates alpha1(I) collagen gene transcription. J Biol Chem, 272(3): 1753-1760
76	Ruiz-Ortega M, Lorenzo O, Egido J (1998). Angiotensin III up-regulates genes involved in kidney damage in mesangial cells and renal interstitial fibroblasts. Kidney Int Suppl, 68(5): S41-S45
77	Sawadogo M, Roeder R G (1985). Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell, 43(1): 165-175
78	Schultz-Cherry S, Lawler J, Murphy-Ullrich J E (1994). The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. J Biol Chem, 269(43): 26783-26788
79	Schultz-Cherry S, Murphy-Ullrich J E (1993). Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol, 122(4): 923-932
80	Shankland S J, Scholey J W, Ly H, Thai K (1994). Expression of transforming growth factor-beta 1 during diabetic renal hypertrophy. Kidney Int, 46(2): 430-442
81	Sharma K, Eltayeb B O, McGowan T A, Dunn S R, Alzahabi B, Rohde R, Ziyadeh F N, Lewis E J (1999). Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients. Am J Kidney Dis, 34(5): 818-823
82	Sharma K, Jin Y, Guo J, Ziyadeh F N (1996). Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes, 45(4): 522-530
83	Sharma K, Ziyadeh F N (1994). Renal hypertrophy is associated with upregulation of TGF-beta 1 gene expression in diabetic BB rat and NOD mouse. Am J Physiol, 267(6 Pt 2): F1094-F01
84	Sharma K, Ziyadeh F N, Alzahabi B, McGowan T A, Kapoor S, Kurnik B R, Kurnik P B, Weisberg L S (1997). Increased renal production of transforming growth factor-beta1 in patients with type II diabetes. Diabetes, 46(5): 854-859
85	Shi L, Nikolic D, Liu S, Lu H, Wang S (2009). Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice. Am J Physiol Renal Physiol, 296(2): F257-F265
86	Singh R, Alavi N, Singh A K, Leehey D J (1999). Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. Diabetes, 48(10): 2066-2073
87	Singh R, Singh A K, Leehey D J (2005). A novel mechanism for angiotensin II formation in streptozotocin-diabetic rat glomeruli. Am J Physiol Renal Physiol, 288(6): F1183-F1190
88	Sirito M, Lin Q, Deng J M, Behringer R R, Sawadogo M (1998). Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. Proc Natl Acad Sci USA, 95(7): 3758-3763
89	Sirito M, Lin Q, Maity T, Sawadogo M (1994). Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res, 22(3): 427-433
90	Skyler J S (1996). Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am, 25(2): 243-254
91	Sonneveld R, van der Vlag J, Baltissen M P, Verkaart S A, Wetzels J F, Berden J H, Hoenderop J G, Nijenhuis T (2014). Glucose specifically regulates TRPC6 expression in the podocyte in an AngII-dependent manner. Am J Pathol, 184(6): 1715-1726
92	Taipale J, Lohi J, Saarinen J, Kovanen P T, Keski-Oja J (1995). Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem, 270(9): 4689-4696
93	Tamura J, Konno A, Hashimoto Y, Kon Y (2005). Upregulation of renal renin-angiotensin system in mouse diabetic nephropathy. Jpn J Vet Res, 53(1-2): 13-26
94	Vallet V S, Henrion A A, Bucchini D, Casado M, Raymondjean M, Kahn A, Vaulont S (1997). Glucose-dependent liver gene expression in upstream stimulatory factor 2-/- mice. J Biol Chem, 272(35): 21944-21949
95	Vasanthakumar R, Mohan V, Anand G, Deepa M, Babu S, Aravindhan V (2015). Serum IL-9, IL-17, and TGF-β levels in subjects with diabetic kidney disease (CURES-134). Cytokine, 72(1): 109-112
96	Velez J C, Bland A M, Arthur J M, Raymond J R, Janech M G (2007). Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes. Am J Physiol Renal Physiol, 293(1): F398-F407
97	Vidotti D B, Casarini D E, Cristovam P C, Leite C A, Schor N, Boim M A (2004). High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells. Am J Physiol Renal Physiol, 286(6): F1039-F1045
98	Visavadiya N P, Li Y, Wang S (2011). High glucose upregulates upstream stimulatory factor 2 in human renal proximal tubular cells through angiotensin II-dependent activation of CREB. Nephron, Exp Nephrol, 117(3): e62-e70
99	Wang S, Skorczewski J, Feng X, Mei L, Murphy-Ullrich J E (2004). Glucose up-regulates thrombospondin 1 gene transcription and transforming growth factor-beta activity through antagonism of cGMP-dependent protein kinase repression via upstream stimulatory factor 2. J Biol Chem, 279(33): 34311-34322
100	Wang W, Qiu L, Howard A, Solis N, Li C, Wang X, Kopp J B, Levi M (2014). Protective effects of aliskiren and valsartan in mice with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst, 15(4): 384-395
101	Wang Z, Ni J, Shao D, Liu J, Shen Y, Zhou L, Huang Y, Yu C, Wang J, Xue H, Lu L (2013). Elevated transcriptional co-activator p102 mediates angiotensin II type 1 receptor up-regulation and extracellular matrix overproduction in the high glucose-treated rat glomerular mesangial cells and isolated glomeruli. Eur J Pharmacol, 702(1-3): 208-217
102	Weigert C, Brodbeck K, Sawadogo M, Haring H U, Schleicher E D (2004). USF proteins induce human TGF-beta1 gene activation via the glucose response element -1013/-1002 in mesangial cells- upregulation of USF activity by the hexosamine biosynthetic pathway. J Biol Chem, 2: 2
103	White K E (2006). Research into the glomerular podocyte—is it relevant to diabetic nephropathy? Diabet Med, 23(7): 715-719
104	Wong D W, Oudit G Y, Reich H, Kassiri Z, Zhou J, Liu Q C, Backx P H, Penninger J M, Herzenberg A M, Scholey J W (2007). Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol, 171(2): 438-451
105	Yamout H, Lazich I, Bakris G L (2014). Blood pressure, hypertension, RAAS blockade, and drug therapy in diabetic kidney disease. Adv Chronic Kidney Dis, 21(3): 281-286
106	Yoo T H, Li J J, Kim J J, Jung D S, Kwak S J, Ryu D R, Choi H Y, Kim J S, Kim H J, Han S H, Lee J E, Han D S, Kang S W (2007). Activation of the renin-angiotensin system within podocytes in diabetes. Kidney Int, 71(10): 1019-1027
107	Young B A, Johnson R J, Alpers C E, Eng E, Gordon K, Floege J, Couser W G, Seidel K (1995). Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int, 47(3): 935-944
108	Zhang S L, To C, Chen X, Filep J G, Tang S S, Ingelfinger J R, Chan J S (2002). Essential role(s) of the intrarenal renin-angiotensin system in transforming growth factor-beta1 gene expression and induction of hypertrophy of rat kidney proximal tubular cells in high glucose. J Am Soc Nephrol, 13(2): 302-312
109	Zhang Z, Shahinfar S, Keane W F, Ramjit D, Dickson T Z, Gleim G W, Mogensen C E, de Zeeuw D, Brenner B M, Snapinn S M (2005). Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. J Am Soc Nephrol, 16(6): 1775-1780
110	Zhu Y, Casado M, Vaulont S, Sharma K (2005). Role of upstream stimulatory factors in regulation of renal transforming growth factor-beta1. Diabetes, 54(7): 1976-1984
111	Ziyadeh, F. N. (2004). Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J Am Soc Nephrol, 15 (Suppl 1), S55-57
112	Ziyadeh F N, Sharma K, Ericksen M, Wolf G (1994). 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, 93(2): 536-542