Journal of Diabetes & Metabolism

ISSN - 2155-6156

Review Article - (2013) Volume 0, Issue 0

Pathogenic Role of TGF- β in Diabetic Nephropathy

Hyun Soon Lee*
Renal Pathology Laboratory, Hankook Kidney and Diabetes Institute, Korea
*Corresponding Author: Hyun Soon Lee, Renal Pathology Laboratory, Hankook Kidney and Diabetes Institute, Songpa-gu, Samhaksaro 93, Seoul, 138- 840, Korea, Tel: 82-2-420-3620, Fax: 82-2-420-3622 Email:


About one-third of diabetic patients develop diabetic kidney disease. In renal cells, transforming growth factor- β (TGF-β) is a key regulator of extracellular matrix protein synthesis and is secreted as latent complexes. Chronic hyperglycemia in diabetic patients seems to stimulate the glomerular mesangial cells to secrete TGF- β, which is stored in the mesangial matrix and then localized to the podocyte surface. Glomerular hypertension in the diabetic kidney may upregulate angiotensin II (Ang II) in podocytes, which may activate the latent TGF- β. Activated TGF- β /Smad signaling may stimulate the podocytes to overproduce α3(IV) collagen, leading to glomerular basement membrane (GBM) thickening. Furthermore, TGF-β-induced connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) may stimulate mesangial cells to overproduce matrix, culminating in diabetic glomerulo sclerosis. TGF-β- induced podocyte loss may also contribute to the development of glomerulosclerosis. Together, this review provides new mechanistic insights into the renal activation of TGF-ß signaling and TGF-ß-induced glomerular pathology in diabetic nephropathy.

Keywords: CTGF; GBM thickening; Glomerulosclerosis; Hyperglycemia; Mesangial matrix expansion; TGF- β /Smad signaling; VEGF


Diabetic nephropathy remains the most common cause of endstage renal failure as the incidence of diabetes rises rapidly worldwide [1]. Nearly one-third of patients with diabetes develop nephropathy. Thickening of the glomerular basement membrane (GBM) and accumulation of extracellular matrix (ECM) protein in the mesangium are hallmarks of diabetic nephropathy.

Transforming growth factor-β (TGF-β) is a key regulator of ECM protein synthesis in renal cells. Three mammalian TGF-β isoforms, TGF-β1, -β2, and -β3, are recognized, of which TGF-β1 is the most potent promoter of ECM accumulation. Expression of TGF-β isoforms occurs in different patterns in renal fibrosis. Induction of TGF-β2 and TGF-β3 but not of TGF-β1 was detected in podocytes of rats with passive Heyman nephritis [2]. Anti-Thy1.1 nephritis is associated with transient induction of TGF-β2 in mesangial cells and podocytes [3]. In the acute phase of experimental diabetes, glomerular TGF-β2 protein was most strikingly induced in the absence of changes in TGF-β2 mRNA levels, whereas no increases in the TGF-β1 protein were detected despite elevated TGF-β1 mRNA levels [4].Renal cortical TGF-β1 protein levels, however, were increased during the chronic phase of disease [4].Indeed, upregulation of renal TGF-β1 has been demonstrated in human and experimental diabetes [5-7].

TGF-β1 is secreted as latent complexes, which are stored in the ECM to provide stability to the active molecule and a readily activable source of it [8]. High glucose together with glycated albumin and advanced glycation end product (AGE) induces TGF-β1 in mesangial cells in vitro [9-11], but not in podocytes [12]. Mesangial immunostaining for active TGF-β1, however, is frequently negative in human and rat diabetic nephropathy [13,14], whereas podocytes exhibit increased expression of TGF-β1 [14-18]. In this context, it is proposed that latent TGF-β secreted by mesangial cells is localized to the podocytes and that activated TGF-β in podocytes leads to GBM thickening and mesangial matrix accumulation in diabetic glomeruli [19-21]. The active form of TGF-β, however, has a very short half-life in plasma [22], and it is unlikely for activated TGF-β in podocytes to traverse the GBM to promote mesangial sclerosis. Instead, TGF-β-induced connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) secreted from podocytes seem to traverse the GBM against the flow of glomerular filtration to act upon the mesangial cells [23].

This review will discuss the recent findings on the mechanisms of renal TGF-β activation and TGF-β-induced glomerular pathology in diabetic nephropathy. It will also discuss the mechanisms by which TGF-β- induced CTGF and VEGF could contribute to the development of diabetic nephropathy.

Activation of Latent TGF-β in Diabetic Nephropathy

TGF-β1 is secreted as latent complexes. Some cells secrete TGF-β in the form of a TGF-β/latency-associated peptide (LAP) complex, referred to as the small latent complex. Yet most cells secrete TGF-β as part of a large latent complex, in which latent TGF-β binding protein (LTBP) is linked to the small latent complex. LTBP has an ECM binding region to transport latent TGF-β complex into the ECM [24,25] (Figure 1). The large latent complex is susceptible to proteolysis, within which LTBP is first cleaved. Then soluble large latent TGF-β complex is released from the ECM, and is activated by another proteolytic event that releases TGF-β from LAP [26].


Figure 1: Latent TGF-β complex. TGF-β is associated with a latency-associated peptide (LAP) and forms a small latent complex. To the small latent complex, latent TGF-β binding protein (LTBP) is linked, forming a large latent complex. LTBP has an extracellular matrix (ECM)-binding region to transport latent TGF-β complex into the ECM.

High glucose as well as glycated albumin and AGE induce TGF-β over expression in mesangial cells in culture [9-11], but not in podocytes [12]. In human and experimental diabetic nephropathy, some mesangial cells show immunoreactivity for TGF-β1 [27,28]. Mesangial immunostaining for active TGF-β1, however, is very weak or almost negligible in human diabetic nodular glomerulosclerosis, despite increased mesangial TGF-β1 mRNA and latent TGF-β1 protein expression [14]. Rather, podocytes or the peripheral portion of the sclerotic segments exhibit increased expression of TGF-β1 protein in human diabetic glomerulosclerosis [5,14]. Enhanced expression of glomerular TGF-β1 is also observed mainly in podocytes of diabetic animals [15-17].In this regard, it is proposed that large latent TGF-β complexes secreted by mesangial cells might be stored in the mesangial matrix in diabetic nephropathy, from which incompletely activated latent TGF-βis released and localized to the podocyte surface [19,21,29]. Podocyte-derived plasmin, matrix metalloproteinases (MMPs), thrombospondin-1, and particularly angiotensin II (Ang II)- induced oxidative stress may activate the latent TGF-β in podocytes [20,21] (Figure 2).


Figure 2: Schematic illustration of proposed mechanism of TGF-β action inpodocytes and mesangial cells leading to the development of diabeticnephropathy. High glucose stimulates TGF-β secretion in mesangial cells and TGF-β receptor (TGF-β R’) expression in podocytes. Soluble forms of latent TGF-β complex released from mesangial matrix may be localized to the podocyte surface and activated by angiotensin (Ang) II. Activated TGF-β/ Smad signaling pathway in podocytes mayinduce α3(IV) collagen, connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) overexpression, leading to glomerular basement membrane (GBM)thickening and mesangial matrix expansion, culminating in diabetic glomerulosclerosis.

Induction of TGF-β by Glomerular Hypertension or Biomechanical strain in Diabetic Glomeruli

Glomerular hypertrophy is present in the early phase of diabetic nephropathy. Podocytes in enlarged glomeruli have to cover a larger GBM area and are subjected to increased mechanical stress and injury. Cytoplasmic changes manifested by hypertrophy/degeneration, foot process effacement or widening, and subsequent detachment of the cell body from the GBM with areas of bare GBM were described both in animal and human studies of diabetes [30-33]. In cultured podocytes, albumin load or mechanical strain increases the levels of TGF-β1 and AngII as well as TGF-β receptors [34-36]. Glomerular hemodynamic adaptive changes, such as hyperfiltration and hyperperfusion, seem to promote progressive glomerulosclerosis in patients with reduced nephron mass and diabetes [37]. In the remnant kidney model of glomerular capillary hypertension, TGF-β1 [34] and Ang II type I receptor [35] are upregulated by protein-laden podocytes. Together, an increase in glomerular capillary pressure may stimulate Ang II and TGF-β1 expression in podocytes through mechanical force injury in diabetic nephropathy.

Effects of Ang II on TGF-β signaling in diabetic nephropathy

The renin-angiotensin system (RAS) seems to be involved in podocyte injury through the induction of oxidative stress in diabetic nephropathy [37]. Ang II is a major active product of the RAS. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, and is strongly expressed by podocytes [38]. Ang II may enhance the generation of ROS through the activation of NADPH oxidases in podocytes. Unlike mesangial cells, podocytes do not overexpress TGF-β1 in response to Ang II. Rather, Ang II increases the expression of the TGF-β type II receptor and VEGF in podocytes [39]. Furthermore, Ang II-induced oxidative stress may activate the latent TGF-β and, subsequently, the TGF-β signaling system in diabetic nephropathy [21].

Activated TGF-β and Renal Pathological Changes

Activated TGF-β signals through sequential activation of two cell surface receptor serine-threonine kinases. Upon TGF-β binding, the constitutively active TGF-β type II receptor associates with and phosphorylates the TGF-β type I receptor [40]. Then Smad2 and Smad3 proteins are activated by TGF-β type I receptor kinase. The phosphorylated Smad2 and Smad3 form heteromeric complexes with Smad4, and then translocate to the nucleus, transducing signals to the target genes [41]. Smad3 is strongly activated in experimental diabetic nephropathy [42]. In podocytes, TGF-β1 phosphorylates Smad2 [43,44]. Furthermore, immunostaining for TGF-β1, TGF-β type II receptor and phosphorylated Smad2/Smad3 is increased in damaged podocytes of sclerotic glomerular segments [45]. In this context, TGF-β/Smad2/3 signaling pathway seems to be activated in podocytes of diabetic glomeruli to induce the expression of TGF-β target genes, such as type IV collagen, CTGF and VEGF (Figure 2). Renal fibrotic action of TGF-β/Smad2/3 pathway, however, is negatively regulated by an inhibitory Smad called Smad7, resulting in decreased renal fibrosis [42,46,47].

GBM thickening in relation to TGF-β in diabetic nephropathy

Thickening of the GBM occurs early and is detectable even within a few years after the onset of diabetes [48]. Transgenic diabetic mice with dominant-negative glucose-dependent insulinotropic polypeptide receptor in pancreatic β-cells exhibited slight but significant thickening of the GBM even at 8 week of age, when glomerular size did not differ from controls[17].

Collagen type IV is the main component of the GBM, which includes six genetically distinct isoforms named α1(IV) to α6(IV). In insulin-dependent diabetes, the collagen α3(IV) through α5(IV) chains, collagen V, laminin, fibronectin, and serum proteins contribute to the thickened GBM [49]. TGF-β is known to stimulate the production of type IV collagen, fibronectin and laminin in podocytes [50], particularly α3(IV) collagen [12].In TGF-β1 transgenic mice, GBM thickness was increased as compared with wild-type animals. Furthermore, streptozotocin-induced hyperglycemia aggravated the TGF-β1-induced GBM thickening [51].

High glucose induced VEGF and ligand-binding TGF-β type II receptor expression in podocytes [12,52]. Furthermore, high glucose and exogenous TGF-β1coordinately increased α3(IV) collagen and VEGF expression. Thus, high glucose seems to enhance the effects of ambient TGF-β1 on α3(IV) collagen and VEGF production by increasing the expression of TGF-β type II receptor[12]. AngII also appears to stimulate the podocytes to produce α3(IV) collagen via mechanisms involving TGF-β and VEGF signaling [39] (Figure 2). GBM thickening in diabetic mice is prevented by Smad3 deficiency [53,54] or administration of anti-TGF-β antibody [55]. Collectively, GBM thickening by abnormal deposition of ECM in diabetic nephropathy could be due to enhanced TGF-β/Smad signaling in podocytes (Figure 2).

A further potential mechanism for GBM destruction and thickening involves the action of proteolytic enzymes, such as MMPs. MMP- 9 expression is increased in podocytes in human and experimental diabetic nephropathy [56]. In cultured podocytes, TGF-β1 stimulates the production of MMP-9 [43,56], and many of the MMPs (MMP-3, -9, -10, and -14) are induced by mechanical strain [57]. Together, increased TGF-β1 levels in podocytes may induce MMPs, resulting in proteolytic damage and thickening of the GBM in diabetic nephropathy.

Induction of VEGF and its effects on GBM thickening in diabetic nephropathy: VEGF-A is almost exclusively expressed by podocytes in the developing and mature glomerulus, and plays an essential role in the formation and maintenance of a functional glomerular filtration barrier [58]. In addition, VEGF-A seems to participate in TGF-β1-induced glomerular fibrosis [39,59]. VEGF acts mainly through two receptor tyrosine kinases, VEGF receptor-1 (VEGFR-1) (FLT1, fms-like tyrosine kinase-1) and VEGFR-2 (human KDR, kinase domain receptor; mouse FLK1, fetal liver kinase-1). The classically recognized functions of VEGF are mediated by VEGFR-2. FLT1is produced as soluble (sFLT1) isoforms, and is capable of binding all isoforms of VEGF, limiting the availability of VEGF to signal through VEGFR-2 (FLK1/KDR).Cultured podocytes possess both VEGFR-1 and VEGFR-2 [60,61]. Recently, Jin et al. [62] reported that podocytes in the mouse glomeruli produce sFLT1.Circulating VEGF-A levels are increased in patients with diabetic nephropathy [63]. In the glomeruli of diabetic animals, VEGF is increased in the podocytes [64-66], and VEGF antagonists have renoprotective effects [64,66-68]. By contrast, some authors described that its expression is decreased in the podocytes of patients with diabetic nephropathy, which could be attributed to podocyte loss [69,70]. VEGF increases α3(IV) collagen via VEGFR-1 in cultured podocytes [71]. Podocytes of diabetic animals may also overproduce α3(IV) collagen through VEGF-A/VEGFR-1 autocrine loop. Indeed, diabetic animals with increased VEGF expression in the podocytes show GBM thickening [64-66,72].

Mesangial matrix expansion in diabetic nephropathy: paracrine effector mechanism of CTGF and VEGF for TGF-β to act on mesangial cells

Podocyte-specific injury in transgenic mice induced mesangial expansion and glomerulosclerosis [73]. Mesangial matrix expansion is prevented in Smad3-knockout diabetic mice [53,54], and anti-TGF-β- treated [55,74] or TGF-β type II receptor-deficient [75] diabetic mice. Thus, activation of the TGF-β/Smad signaling in podocytes from the diabetic glomeruli may contribute to overproduction of ECM in the mesangial areas. And yet the podocyte TGF-β is unlikely to traverse the GBM, as its active form has a very short half-life in plasma. Instead, podocyte-derived CTGF and VEGF stimulated by TGF-β might be transported across the GBM to capillary lumen to act upon the mesangial cells [23].

Paracrine effects of podocyte CTGF on mesangial CTGF expression andmesangial matrix expansion: In normal murine or human glomeruli, CTGF is mainly expressed by podocytes [18,76]. TGF-β1 induces CTGF expression in podocytes [77], by the classical Smad pathway via Smad-binding element located within the CTGF promoter [78]. In human diabetic glomeruli, CTGF is overexpressed in mesangial areas and podocytes [14,18,79,80]. Yet conflicting results, possibly related to podocyte loss, were also described [81]. In murine models of diabetic nephropathy, glomerular CTGF protein levels increase initially in podocytes and later in parietal epithelial and mesangial cells [82]. Induction of diabetes in podocyte-specific CTGFtransgenic mice results in an increased mesangial CTGF expression with more severe mesangial expansion than diabetic wild-type mice [76]. Treatment with CTGF antisense oligonucleotides significantly reduced the mesangial matrix expansion in diabetic mice as compared with those receiving mismatch oligonucleotides [83].In mesangial cells, CTGF auto induces its own message [80,84], and stimulates fibronectin [80,84-87], collagen [84,88], plasminogen activator inhibitor-1[80], MMP-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-3 [89] expression. CTGF appears to stimulate the fibronectin-matrix assembly in the mesangium of diabetic glomeruli (for a review, see Lee [23]). In addition, CTGF may increase fibonectin mRNA expression in kidneys of diabetic mice [83]. In sum, TGF-β-induced CTGF by podocytes mayinduce mesangial CTGF overexpressionin diabetic nephropathy leading to mesangial matrix expansion (Figure 2).

Paracrine effects of podocyte VEGF on mesangial matrix expansion: Mesangial expression of VEGF-A and its receptors, FLT- 1 and KDR, is not detected or almost negligible in normal human glomeruli [90]. In contrast, cultured mesangial cells express VEGF [91] and its receptors [90]. Upregulation of mesangial VEGF has been described in humans and animals with diabetic nephropathy [92]. In addition, FLT-1 and KDR are demonstrated in the mesangium of pathologic tissue [90]. Paracrine VEGF-A signaling seems to occur between podocytes and adjacent endothelial cells, which express VEGF receptors [93-95]. Similarly, podocyte VEGF may affect mesangial VEGF-A signaling in diabetic nephropathy. VEGF increases collagen and fibronectin synthesis in cultured mesangial cells [59]. Transgenic rabbits with VEGF overexpression in the kidney showed mesangial matrix expansion and glomerular hypertrophy, leading to the development of glomerulosclerosis [96], while anti-VEGF attenuates mesangial matrix expansion in diabetic mice [97]. Diabetic animals with increased VEGF expression in the podocytes show GBM thickening and mesangial expansion [64-66]. Furthermore, diabetic mice overexpressing podocyte Vegf164 exhibit advanced diabetic glomerulopathy with nodular sclerosis (Kimmelstiel-Wilson lesion) [72].Together, TGF-β-induced VEGF by podocytes may play a paracrine role on mesangial cells to upregulate VEGF/VEGF receptor systems and to overproduce matrix proteins in diabetic nephropathy, resulting in mesangial matrix expansion (Figure 2).

Podocyte Loss in Relation to TGF-β in Diabetic Nephropathy

Podocyte lossisa critical event in the course of diabetic nephropathy and imposes a burden on the remaining cells, which precipitates the development of glomerulosclerosis [98]. Podocyte loss is the strongest predictor of progression of diabetic nephropathy [99]. In the same context, podocyte detachment is related to the classic structural features of diabetic kidney disease and its progression [100].


Enhanced TGF-β activity in podocytes may lead to podocyte apoptosis [101-104]. Furthermore, TGF-β induces dedifferentiation of podocytes that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions [105].

Detachment of podocytes

α3β1 integrin is an adhesion receptor for laminins and type IV collagen, and expressed primarily on podocytes [106]. High glucose decreased α3β1 integrin expression in cultured podocytes [107,108]. Downregulation of α3β1 integrin is observed in the podocytes of diabetic humans and rats with podocytopenia [109,110]. TGF-β1 suppresses the glomerular expression of α3 integrin in nephrotic rats [111]. In cultured podocytes, TGF-β1 and mechanical stretch significantly reduce the α3β1 integrin expression linked to decreased podocyte adhesion and increased apoptosis [36]. Thus, TGF-β1 may reduce podocyte adhesion to the GBM via downregulation of α3β1 integrin, resulting in podocyte depletion in diabetic nephropathy.

Epithelial to Mesenchymal Transition (EMT) of podocytes

In vitro under the influence of TGF-β, podocytes might take on mesenchymal characteristics, and this mesenchymal phenotype may contribute to podocyte dehiscence and loss [112]. Fibroblast specific protein-1, a marker of EMT, is expressed by podocytes in urine and glomeruli of diabetic patients associated with more severe clinical and pathological findings, suggesting that podocyte loss is induced through an EMT [113]. Liu [114] also suggested that EMT could be a primary pathway leading to podocyte dysfunction and detachment in diabetic nephropathy.

Various EMT-related genes, such as CTGF [79], integrin-linked kinase (ILK) [115], PINCH-1 [116], Wnt [117], Snail [56], α-smooth muscle actin [118], and MMP-2 [119], are the targets of TGF-β/Smad signaling in podocytes. Particularly, TGF-β, ILK, and Wnt/β-catenin signals are interconnected, and inhibition of ILK activity ameliorates podocyte Snail induction and EMT [115]. Smad-independent signaling of TGF-β also plays a role in regulating EMT. Together, more severe and/or longer podocyte injury induced by TGF-β may lead to EMT via upregulation of ILK in diabetic nephropathy.

In summary, TGF-β may induce podocyte loss via apoptosis, detachment from the GBM, and EMT of podocytes in diabetic nephropathy contributing to the development of glomerulosclerosis.


Chronic hyperglycemia in diabetic patients may stimulate mesangialcells to secrete TGF-β, which may be stored in mesangial matrix. Soluble forms of latent TGF-β complex released from the mesangial matrix may belocalized to the podocyte surface and activated by Ang II. Activated TGF-β in podocytes may overproduce α3(IV) collagen leading to GBM thickening. Furthermore, TGF-β-induced CTGF and VEGF produced by podocytes may stimulate mesangial cells to overproduce matrix, culminating in diabetic glomerulosclerosis. In addition, TGF-β-induced podocyte loss may contribute to the development of glomerulosclerosis. Together, this review provides new mechanistic insights into the renal TGF-β activation and TGF- β-induced glomerular pathology in diabetic nephropathy. Better understanding of the activation of TGF-β signaling by podocytes and its downstream effectors may provide novel tools for the prevention of progressive diabetic nephropathy.


  1. Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414: 782-787.
  2. Shankland SJ, Pippin J, Pichler RH, Gordon KL, Friedman S, et al. (1996) Differential expression of transforming growth factor-beta isoforms and receptors in experimental membranous nephropathy. Kidney Int 50: 116-124.
  3. Hartner A, Hilgers KF, Bitzer M, Veelken R, Schöcklmann HO (2003) Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis. J Mol Med (Berl) 81: 32-42.
  4. Hill C, Flyvbjerg A, Grønbaek H, Petrik J, Hill DJ, et al. (2000) The renal expression of transforming growth factor-beta isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology 141: 1196-1208.
  5. Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA (1993) Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A 90: 1814-1818.
  6. Shankland SJ, Scholey JW, Ly H, Thai K (1994) Expression of transforming growth factor-beta 1 during diabetic renal hypertrophy. Kidney Int 46: 430-442.
  7. Hong SW, Isono M, Chen S, Iglesias-De La Cruz MC, Han DC, et al. (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: 1653-1663.
  8. Lawrence DA (2001) Latent-TGF-beta: an overview. Mol Cell Biochem 219: 163-170.
  9. Ziyadeh FN, Han DC, Cohen JA, Guo J, Cohen MP (1998) Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-beta system. Kidney Int 53: 631-638.
  10. Kim YS, Kim BC, Song CY, Hong HK, Moon KC, et al. (2001) Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. J Lab Clin Med 138: 59-68.
  11. Lee HS, Moon KC, Song CY, Kim BC, Wang S, et al. (2004) Glycated albumin activates PAI-1 transcription through Smad DNA binding sites in mesangial cells. Am J Physiol Renal Physiol 287: F665-672.
  12. Iglesias-de la Cruz MC, Ziyadeh FN, Isono M, Kouahou M, Han DC, et al. (2002) Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int 62: 901-913.
  13. Ceol M, Gambaro G, Sauer U, Baggio B, Anglani F, et al. (2000) Glycosaminoglycan therapy prevents TGF-beta1 overexpression and pathologic changes in renal tissue of long-term diabetic rats. J Am Soc Nephrol 11: 2324-2336.
  14. Wahab NA, Schaefer L, Weston BS, Yiannikouris O, Wright A, et al. (2005) Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli. Diabetologia 48: 2650-2660.
  15. Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, et al. (2005) Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol 16: 3222-3234.
  16. Okada T, Wada J, Hida K, Eguchi J, Hashimoto I, et al. (2006) Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms. Diabetes 55: 1666-1677.
  17. Herbach N, Schairer I, Blutke A, Kautz S, Siebert A, et al. (2009) Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis. Am J Physiol Renal Physiol 296: F819-829.
  18. Ito Y, Goldschmeding R, Kasuga H, Claessen N, Nakayama M, et al. (2010) Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis. Am J Physiol Renal Physiol 299: F545-558.
  19. Lee HS, Song CY (2009) Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. Histol Histopathol 24: 901-908.
  20. Lee HS (2011) Pathogenic role of TGF-β in the progression of podocyte diseases. Histol Histopathol 26: 107-116.
  21. Lee HS (2012) Mechanisms and consequences of TGF-β overexpression by podocytes in progressive podocyte disease. Cell Tissue Res 347: 129-140.
  22. Coffey RJ Jr, Kost LJ, Lyons RM, Moses HL, LaRusso NF (1987) Hepatic processing of transforming growth factor beta in the rat. Uptake, metabolism, and biliary excretion. J Clin Invest 80: 750-757.
  23. Lee HS (2012) Paracrine role for TGF-β-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease. Histol Histopathol 27: 1131-1141.
  24. Hyytiäinen M, Penttinen C, Keski-Oja J (2004) Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci 41: 233-264.
  25. Koli K, Myllärniemi M, Keski-Oja J, Kinnula VL (2008) Transforming growth factor-beta activation in the lung: focus on fibrosis and reactive oxygen species. Antioxid Redox Signal 10: 333-342.
  26. Koli K, Saharinen J, Hyytiäinen M, Penttinen C, Keski-Oja J (2001) Latency, activation, and binding proteins of TGF-beta. Microsc Res Tech 52: 354-362.
  27. Iwano M, Kubo A, Nishino T, Sato H, Nishioka H, et al. (1996) Quantification of glomerular TGF-beta 1 mRNA in patients with diabetes mellitus. Kidney Int 49: 1120-1126.
  28. Park IS, Kiyomoto H, Abboud SL, Abboud HE (1997) Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes. Diabetes 46: 473-480.
  29. Lee HS (2011) Role of TGF-β in mesangial matrix accumulation in chronic progressive glomerular disease. In: An Update on Glomerulopathies-Etiology and Pathogenesis. Chapter 7.Prabhakar S (ed)InTech Rijeka, Croatia 123-140.
  30. Murata I, Takemura G, Asano K, Sano H, Fujisawa K, et al. (2002) Apoptotic cell loss following cell proliferation in renal glomeruli of Otsuka Long-Evans Tokushima Fatty rats, a model of human type 2 diabetes. Am J Nephrol 22: 587-595.
  31. Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, et al. (2003) Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 52: 1031-1035.
  32. Kumar D, Robertson S, Burns KD (2004) Evidence of apoptosis in human diabetic kidney. Mol Cell Biochem 259: 67-70.
  33. Petermann AT, Pippin J, Krofft R, Blonski M, Griffin S, et al. (2004) Viable podocytes detach in experimental diabetic nephropathy: potential mechanism underlying glomerulosclerosis. Nephron Exp Nephrol 98: e114–e123.
  34. Abbate M, Zoja C, Morigi M, Rottoli D, Angioletti S, et al. (2002) Transforming growth factor-beta1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins: a central pathway in progressive glomerulosclerosis. Am J Pathol 161: 2179-2193.
  35. Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, et al. (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65: 30-39.
  36. Dessapt C, Baradez MO, Hayward A, Dei Cas A, Thomas SM, et al. (2009) Mechanical forces and TGFbeta1 reduce podocyte adhesion through alpha3beta1 integrin downregulation. Nephrol Dial Transplant 24: 2645-2655.
  37. Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4: 39-45.
  38. Tojo A, Asaba K, Onozato ML (2007) Suppressing renal NADPH oxidase to treat diabetic nephropathy. Expert Opin Ther Targets 11: 1011-1018.
  39. Chen S, Lee JS, Iglesias-de la Cruz MC, Wang A, Izquierdo-Lahuerta A, et al. (2005) Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy. Nephrol Dial Transplant 20: 1320-1328.
  40. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425: 577-584.
  41. Miyazono K, ten Dijke P, Heldin CH (2000) TGF-beta signaling by Smad proteins. Adv Immunol 75: 115-157.
  42. Isono M, Chen S, Hong SW, Iglesias-de la Cruz MC, Ziyadeh FN (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: 1356-1365.
  43. Liu S, Liang Y, Huang H, Wang L, Li Y, et al. (2005) ERK-dependent signaling pathway and transcriptional factor Ets-1 regulate matrix metalloproteinase-9 production in transforming growth factor-beta1 stimulated glomerular podocytes. Cell Physiol Biochem 16: 207-216.
  44. Schiffer M, Mundel P, Shaw AS, Böttinger EP (2004) A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem 279: 37004-37012.
  45. Kim JH, Kim BK, Moon KC, Hong HK, Lee HS (2003) Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis. Kidney Int 64: 1715-1721.
  46. Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, et al. (2002) Inhibitory smads and tgf-Beta signaling in glomerular cells. J Am Soc Nephrol 13: 2657-2666.
  47. Chen HY, Huang XR, Wang W, Li JH, Heuchel RL, et al. (2011) The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes 60: 590-601.
  48. Drummond K, Mauer M; International Diabetic Nephropathy Study Group (2002) The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 51: 1580-1587.
  49. Miner JH (1999) Renal basement membrane components. Kidney Int 56: 2016-2024.
  50. Nakamura T, Miller D, Ruoslahti E, Border WA (1992) Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int 41: 1213-1221.
  51. Krag S, Nyengaard JR, Wogensen L (2007) Combined effects of moderately elevated blood glucose and locally produced TGF-beta1 on glomerular morphology and renal collagen production. Nephrol Dial Transplant 22: 2485-2496.
  52. Hoshi S, Nomoto K, Kuromitsu J, Tomari S, Nagata M (2002) High glucose induced VEGF expression via PKC and ERK in glomerular podocytes. Biochem Biophys Res Commun 290: 177-184.
  53. Fujimoto M, Maezawa Y, Yokote K, Joh K, Kobayashi K, et al. (2003) Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochem Biophys Res Commun 305: 1002-1007.
  54. Wang A, Ziyadeh FN, Lee EY, Pyagay PE, Sung SH, et al. (2007) Interference with TGF-beta signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria. Am J Physiol Renal Physiol 293: F1657-1665.
  55. Chen S, Iglesias-de la Cruz MC, Jim B, Hong SW, Isono M, et al. (2003) Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies in db/db mice. Biochem Biophys Res Commun 300: 16-22.
  56. Li Y, Kang YS, Dai C, Kiss LP, Wen X, et al. (2008) Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am J Pathol 172: 299-308.
  57. Meehan DT, Delimont D, Cheung L, Zallocchi M, Sansom SC, et al. (2009) Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney Int 76: 968-976.
  58. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, et al. (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111: 707-716.
  59. Wang L, Kwak JH, Kim SI, He Y, Choi ME (2004) Transforming growth factor-β1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38? and p38? mitogen-activated protein kinase-dependent pathway in murine mesangial cells. J Biol Chem 279: 33213-33219.
  60. Guan F, Villegas G, Teichman J, Mundel P, Tufro A (2006) Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP. Am J Physiol Renal Physiol 291: F422-428.
  61. Müller-Deile J, Worthmann K, Saleem M, Tossidou I, Haller H, et al. (2009) The balance of autocrine VEGF-A and VEGF-C determines podocyte survival. Am J Physiol Renal Physiol 297: F1656-1667.
  62. Jin J, Sison K, Li C, Tian R, Wnuk M, et al. (2012) Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151: 384-399.
  63. Hovind P, Tarnow L, Oestergaard PB, Parving HH (2000) Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Kidney Int Suppl 75: S56-61.
  64. Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, et al. (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48: 2229-2239.
  65. Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, et al. (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162: 1123-1137.
  66. Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, et al. (2006) Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 17: 3093-3104.
  67. de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, et al. (2001) Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 12: 993-1000.
  68. Schrijvers BF, Flyvbjerg A, De Vriese AS (2004) The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int 65: 2003-2017.
  69. Shulman K, Rosen S, Tognazzi K, Manseau EJ, Brown LF (1996) Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 7: 661-666.
  70. Bailey E, Bottomley MJ, Westwell S, Pringle JH, Furness PN, et al. (1999) Vascular endothelial growth factor mRNA expression in minimal change, membranous, and diabetic nephropathy demonstrated by non-isotopic in situ hybridisation. J Clin Pathol 52: 735-738.
  71. Chen S, Kasama Y, Lee JS, Jim B, Marin M, et al. (2004)Podocyte-derived vascular endothelial growth factor mediates the stimulation of ?3(IV) collagen production by transforming growth factor-β1 in mouse podocytes. Diabetes 53: 2939-2949.
  72. Veron D, Bertuccio CA, Marlier A, Reidy K, Garcia AM, et al. (2011) Podocyte vascular endothelial growth factor (Vegf₁₆₄) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 54: 1227-1241.
  73. Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, et al. (2005) Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury. J Am Soc Nephrol 16: 1013-1023.
  74. Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, et al. (2000) 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 U S A 97: 8015-8020.
  75. Kim HW, Kim BC, Song CY, Kim JH, Hong HK, et al. (2004) Heterozygous mice for TGF-betaIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy. Kidney Int 66: 1859-1865.
  76. Yokoi H, Mukoyama M, Mori K, Kasahara M, Suganami T, et al. (2008) Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int 73: 446-455.
  77. Ito Y, Goldschmeding R, Bende R, Claessen N, Chand M, et al. (2001) Kinetics of connective tissue growth factor expression during experimental proliferative glomerulonephritis. J Am Soc Nephrol 12: 472-484.
  78. Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, et al. (2001) CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 276: 10594-10601.
  79. Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, et al. (1998) Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 53: 853-861.
  80. Wahab NA, Yevdokimova N, Weston BS, Roberts T, Li XJ, et al. (2001) Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J 359: 77-87.
  81. Baelde HJ, Eikmans M, Lappin DW, Doran PP, Hohenadel D, et al. (2007) Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int 71: 637-645.
  82. Roestenberg P, van Nieuwenhoven FA, Joles JA, Trischberger C, Martens PP, et al. (2006) Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice. Am J Physiol Renal Physiol 290: F1344-1354.
  83. Guha M, Xu ZG, Tung D, Lanting L, Natarajan R (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J 21: 3355-3368.
  84. Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, et al. (2000) Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 11: 25-38.
  85. Blom IE, van Dijk AJ, Wieten L, Duran K, Ito Y, et al. (2001) In vitro evidence for differential involvement of CTGF, TGFbeta, and PDGF-BB in mesangial response to injury. Nephrol Dial Transplant 16: 1139-1148.
  86. Crean JKG, Finlay D, Murphy M, Moss C, Godson C, et al. (2002) The role of p42/44 MAPK and protein kinase B in connective tissue growth factor induced extracellular matrix protein production, cell migration, and actin cytoskeletal rearrangement in human mesangial cells. J Biol Chem 277: 44187-4419.
  87. Weston BS, Wahab NA, Mason RM (2003) CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5beta1 integrin in human mesangial cells. J Am Soc Nephrol 14: 601-610.
  88. Gore-Hyer E, Shegogue D, Markiewicz M, Lo S, Hazen-Martin D, et al. (2002) TGF-beta and CTGF have overlapping and distinct fibrogenic effects on human renal cells. Am J Physiol Renal Physiol 283: F707-716.
  89. McLennan SV, Wang XY, Moreno V, Yue DK, Twigg SM (2004) Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: implications for diabetic nephropathy. Endocrinology 145: 5646-5655.
  90. Thomas S, Vanuystel J, Gruden G, Rodríguez V, Burt D, et al. (2000) Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease. J Am Soc Nephrol 11: 1236-1243.
  91. Iijima K, Yoshikawa N, Connolly DT, Nakamura H (1993) Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor. Kidney Int 44: 959-966.
  92. Tsuchida K, Makita Z, Yamagishi S, Atsumi T, Miyoshi H, et al. (1999) Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia 42: 579-588.
  93. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9: 669-676.
  94. Foster RR (2009) The importance of cellular VEGF bioactivity in the development of glomerular disease. Nephron Exp Nephrol 113: e8-8e15.
  95. Sison K, Eremina V, Baelde H, Min W, Hirashima M, et al. (2010) Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J Am Soc Nephrol 21: 1691-1701.
  96. Liu E, Morimoto M, Kitajima S, Koike T, Yu Y, et al. (2007) Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. J Am Soc Nephrol 18: 2094-2104.
  97. Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, Schrijvers BF, Tilton RG, et al. (2002) Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes 51: 3090-3094.
  98. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, et al. (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99: 342-348.
  99. Meyer TW, Bennett PH, Nelson RG (1999) Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 42: 1341-1344.
  100. Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, et al. (2012) Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int 82: 1010-1017.
  101. Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P, et al. (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 108: 807-816.
  102. Wu DT, Bitzer M, Ju W, Mundel P, Böttinger EP (2005) TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol 16: 3211-3221.
  103. Susztak K, Raff AC, Schiffer M, Böttinger EP (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55: 225-233.
  104. Lee HS, Song CY (2010) Effects of TGF-beta on podocyte growth and disease progression in proliferative podocytopathies. Kidney Blood Press Res 33: 24-29.
  105. Herman-Edelstein M, Thomas MC, Thallas-Bonke V, Saleem M, Cooper ME, et al. (2011) Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy. Diabetes 60: 1779-1788.
  106. Kreidberg JA, Symons JM (2000) Integrins in kidney development, function, and disease. Am J Physiol Renal Physiol 279: F233-242.
  107. Kretzler M (2002) Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech 57: 247-253.
  108. Kitsiou PV, Tzinia AK, Stetler-Stevenson WG, Michael AF, Fan WW, et al. (2003) Glucose-induced changes in integrins and matrix-related functions in cultured human glomerular epithelial cells. Am J Physiol Renal Physiol 284: F671-679.
  109. Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, et al. (2000) Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci 67: 2345-2353.
  110. Regoli M, Bendayan M (1997) Alterations in the expression of the alpha 3 beta 1 integrin in certain membrane domains of the glomerular epithelial cells (podocytes) in diabetes mellitus. Diabetologia 40: 15-22.
  111. Kagami S, Border WA, Ruoslahti E, Noble NA (1993) Coordinated expression of beta 1 integrins and transforming growth factor-beta-induced matrix proteins in glomerulonephritis. Lab Invest 69: 68-76.
  112. Reidy K, Susztak K (2009) Epithelial-mesenchymal transition and podocyte loss in diabetic kidney disease. Am J Kidney Dis 54: 590-593.
  113. Yamaguchi Y, Iwano M, Suzuki D, Nakatani K, Kimura K, et al. (2009) Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis 54: 653-664.
  114. Liu Y (2010) New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21: 212-222.
  115. Kang YS, Li Y, Dai C, Kiss LP, Wu C, et al. (2010) Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria. Kidney Int 78: 363-373.
  116. Jung KY, Chen K, Kretzler M, Wu C (2007) TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells. J Am Soc Nephrol 18: 66-73.
  117. Wang D, Dai C, Li Y, Liu Y (2011) Canonical Wnt/β-catenin signaling mediates transforming growth factor-β1-driven podocyte injury and proteinuria. Kidney Int 80: 1159-1169.
  118. Chen CA, Hwang JC, Guh JY, Tsai JC, Chen HC (2006) TGF-beta1 and integrin synergistically facilitate the differentiation of rat podocytes by increasing alpha-smooth muscle actin expression. Transl Res 148: 134-141.
  119. Asanuma K, Shirato I, Ishidoh K, Kominami E, Tomino Y (2002) Selective modulation of the secretion of proteinases and their inhibitors by growth factors in cultured differentiated podocytes. Kidney Int 62: 822-831.
Citation: Lee HS (2013) Pathogenic Role of TGF- β in Diabetic Nephropathy. J Diabetes Metab S9:008.

Copyright: © 2013 Lee HS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.