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TGF-β signaling in diabetic nephropathy: An update

Published Online: 29 Jun 2022
Volume & Issue: AHEAD OF PRINT
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Received: 29 Dec 2020
Accepted: 11 May 2022
Journal Details
License
Format
Journal
eISSN
2719-3500
First Published
30 Jun 2021
Publication timeframe
4 times per year
Languages
English
Abstract

Diabetic nephropathy (DN) is a common complication in patients with diabetes and the leading cause of end-stage renal disease. Accumulating evidence shows that transforming growth factor beta-1 (TGF-β1) is a key mediator in the pathogenesis of DN. TGF-β1 binds to its receptors to activate canonical and noncanonical downstream signaling pathways to exert its biological activities. Among them, canonical Smad signaling is the major pathway responsible for the development of DN. In addition to TGF-β1, many stress molecules, such as advanced glycation end products (AGEs), angiotensin II (Ang II), and C-reactive protein (CRP), can also activate Mothers against decapentaplegic homologs (Smads) via the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) cross talk mechanism. Furthermore, TGF-β/Smad signaling can also cross talk with nuclear factor kappa B (NF-κB) signaling to regulate renal inflammation via the induction of IκBα by Smad7. In the context of renal fibrosis, Smad3 is pathogenic, while Smad2 and Smad7 are protective. TGF-β signaling also upregulates the pathogenic microRNAs (miRNAs) (namely, miR-21, miR-192, and miR-377) and long noncoding RNAs (lncRNAs) (namely, Erbb4-IR (intron region, IR), LncRNA9884, and Arid2-IR) but downregulates the protective miRNAs (namely, miR-29a/b and miR-200a) to mediate DN. Thus, targeting TGF-β signaling, either by blocking its ligand, its receptor (i.e., TGF-β receptor-2 [TGFBR2]), Smad3, and downstream miRNAs/lncRNAs or by overexpressing Smad7, has been shown to improve DN. In addition, pharmaceutically targeting TGF-β signaling using chemical inhibitors and traditional Chinese medicine (TCM), including Tangshen formula, Chaihuang-Yishen granule, and herbal extracts (berberine, asiatic acid, and naringenin), also shows renoprotective effect in diabetes. In summary, TGF-β signaling is a critical pathway leading to DN and may be a therapeutic target for combating DN.

Keywords

Introduction

Diabetic nephropathy (DN) is one of the most common complications in both type-1 and type-2 diabetes mellitus. With the prevalence of diabetes, DN has become the primary cause of end-stage renal disease worldwide [1, 2]. Pathologically, DN is characterized by glomerular hypertrophy, mesangial expansion, glomerular basement membrane (GBM) thickening, podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and renal inflammation, which is accompanied by proteinuria, increased serum creatinine, and eventually the fall of glomerular filtration rate [2, 3]. Various mediators and signaling mechanisms play pivotal roles in the pathogenesis of DN, which also include the cytokine transforming growth factor beta (TGF-β).

TGF-β1 is a well-known prosclerotic/profibrotic cytokine that functions to induce the expression of extracellular matrix (ECM) components and thus causes tissue fibrosis, including the development of DN [4]. The pathogenic role of TGF-β1 in fibrosis is demonstrated by the findings that mice overexpressing Tgfb1 develop fibrosis in multiple organs, including the kidney, liver, heart, blood vessel, pancreas, and testis [5,6,7,8]. This has also been found in diabetic Akita mice (a rodent model of DN) in which hypermorphic but not hypomorphic expression of Tgfb1 aggravates the typic features of DN, including increased glomerulosclerosis, glomerular mesangial expansion, and proteinuria [9]. Clinically, patients with DN exhibit elevated levels of plasma and urinary TGF-β1, which positively correlates with the severity of disease, including progressive renal fibrosis [10,11,12,13]. It is now well known that after binding to receptors, TGF-β can activate its downstream signaling, including Smad-dependent and -independent pathways, to mediate renal fibrosis [4]. Under diabetic conditions, TGF-β signaling is highly activated in the diabetic kidney in patients and experimental animal models [1, 14,15,16,17]. In this review, we focus on the roles and signaling mechanisms of TGF-β in the pathogenesis of DN. The recent progress in the development of anti-DN therapy by targeting TGF-β signaling is also highlighted.

Overview of TGF-b Signaling

TGF-β belongs to the TGF superfamily, which also contains the signaling molecules bone morphogenetic protein (BMP), growth and differentiation factor (GDF), activin, and nodal [18]. TGF-β exerts its functions by binding to the transmembrane type-2 serine/threonine kinase receptor TGFBR2, resulting in the recruitment and activation of the type-1 receptor TGFBR1 by phosphorylation. Then, the activated TGFBR1 can initiate the activation of both Smad-dependent (canonical) and -independent (noncanonical) pathways to exert its biological activities [1, 4]. In the Smad-dependent pathway, the activated TGFBR1 can phosphorylate the cytosolic receptor-regulated Mothers against decapentaplegic homolog (Smad) proteins (R-Smads) Smad2 and Smad3, which then form a complex with Smad4 (common Smad or Co-Smad) and translocate into the nucleus to regulate target gene transcription [1, 4, 18]. Smad7 is an inhibitory Smad protein induced by TGF-β1, but it functions to counterbalance the TGF-β signaling activity by competitively binding to TGFBR1 and inducing its degradation (Figure 1) [19, 20]. In addition to the canonical TGF-β/Smad signaling, TGF-β ligand can also induce Smad-independent signaling, such as MAPK, phosphoinositide 3-kinase (PI3K), and small guanosine triphosphatase (GTPase) pathways [1, 4]. Furthermore, the R-Smads can also be activated through TGF-β ligand-independent pathways by cross talk with MAPK signaling [18]. These diverse regulatory networks add additional complexity and plasticity to TGF-β signaling. The blueprint of TGF-β signaling is illustrated in Figure 1, and the reader can also refer to other review articles for a more comprehensive description [1, 18, 21].

Figure 1

Regulatory pathways of TGF-β signaling in DN. Smad2/3 can be activated by both TGF-β-dependent and -independent mechanisms. Many stress molecules such as Ang II, AGE, and CRP can activate Smad2/3 to exert their biological effects via cross talk with ERK/p38 MAPK pathway. High glucose promotes the activation of latent TGF-β ligand and the transcription of Tgfb1 and Tgfbr2. In addition, Smad7 functions to counteract Smad2/3 signaling via the negative feedback loop and suppresses NF-κB activation by inducing IκBα. The red line indicates pathogenic, whereas the green line implies protective, pathways. The arrow stands for positive regulation, and the blunt line represents negative regulation. AGE, advanced glycation end product; Ang II, angiotensin II; AT1/2, Ang II type 1/2 receptor; CD, cluster of differentiation; CRP, C-reactive protein; DN, diabetic nephropathy; Erk, extracellular signal-regulated kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; RAGE, receptor of AGE; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.

Role and Mechanisms of TGF-b Signaling in DN

Patients with DN usually experience hyperglycemia, hyper-lipidemia, and hypertension [22]. It is now clear that many hazardous factors, such as high glucose, advanced glycation end products (AGEs), angiotensin II (Ang II), and C-reactive protein (CRP), can activate Smad signaling via both TGF-β ligand-dependent and -independent mechanisms (Figure 1). Under diabetic conditions, high glucose can activate TGF-β signaling via several mechanisms, including the induction of thrombospondin 1 (TSP1), to convert inactive latent TGF-β1 into the active form and thus leading to upregulation of TGF-β1 and TGFBR2 [16, 17, 23,24,25,26,27]. AGEs are glycation products of proteins or lipids in the condition of hyperglycemia and widely deposited in local tissues, including kidney, in patients with diabetes [28]. AGE can induce the rapid (within 30 min) phosphorylation of Smad2 and Smad3 via the receptor of AGE (RAGE)-mediated extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) signaling cross talk in tubular epithelial cells (TECs) and mesangial cells (MCs) through a TGF-β-independent pathway (Figure 1) [14, 29]. AGE also induces TGF-β production, leading to the stimulation of classic TGF-β signaling to maintain subsequent long-term activation of downstream Smad signaling in a TGF-β-dependent manner [14].

Ang II is a key mediator of hypertension and can also rapidly phosphorylate Smad2/3 through ERK/p38 MAPK signaling cross talk in vascular smooth muscle cells (VSMCs) and TECs via a TGF-β-independent manner (Figure 1) [30,31,32]. Similar to AGEs, Ang II also induces the long-term activation of Smad2/3 in a TGF-β-dependent way [31]. In addition to MAPK, Ang II also induces de novo TGF-β1 expression via the protein kinase C (PKC)-dependent pathway [33, 34].

CRP is an acute-phase protein that is a biomarker of systemic inflammation. It is reported that elevated blood CRP level is associated with the occurrence of diabetes and DN [35, 36]. Transgenic overexpression of human CRP exaggerates the severity of renal injury in both type-1 and type-2 diabetic mouse models [37, 38]. After binding to its receptor cluster of differentiation-32 (CD32), CRP rapidly activates Smad3 via ERK/p38 MAPK signal cross talk in a TGF-β-independent manner. Similar to AGE and Ang II, CRP also triggers long-term Smad3 activation by inducing TGF-β1 expression (Figure 1) [37].

Free fatty acids can also activate TGF-β signaling as the addition of palmitate (a common saturated free fatty acid) can induce TGF-β1 expression and activate downstream Smad2/3 signaling through the CD36-mediated transient receptor potential cation channel subfamily C member 6/nuclear factor of activated T-cells 2 (TRPC6/NFAT2) pathway in human MCs [39].

As described earlier, TGF-β1 is highly upregulated in patients with DN and is induced by various DN-associated risk factors [10,11,12, 23, 24, 40]. The pathogenic role of TGF-β1 in DN can be perceived from the fact that transgenic Tgfb1 overexpression directly induces renal injury with features of DN, including glomerulosclerosis and protein-uria [5, 8, 41, 42]. Further, in a DN model of Akita mice with a finely modified expression of endogenous Tgfb1, hypermorphic Tgfb1 expression aggravates, while hypomorphic Tgfb1 expression attenuates or even prevents, DN phenotypes [9]. On the other hand, blocking TGF-β by in vivo delivery of a neutralizing antibody, antisense oligodeoxynucleotide, and soluble TGFBR2 ameliorates renal injury in experimental diabetic animals [43,44,45,46,47]. In vitro, high glucose-triggered ECM production can also be reversed by a neutralizing antibody against TGF-βs [48]. These findings confirm the role of TGF-β1 as a critical pathogenic mediator in DN.

TGFBR also plays a vital role in DN. Although the TGFBR2-null mutation is embryonically lethal, heterozygous deletion of TGFBR2 (Tgfbr2+/−) inhibits Smad2/3 signaling and improves renal function by significantly attenuating urinary protein secretion, which is accompanied by substantially alleviated glomerular hypertrophy, mesangial expansion, and glomerulosclerosis in streptozocin (STZ)-induced DN [49].

Although both Smad2 and Smad3 are R-Smads and share high similarity in terms of amino acid sequence, structure, and DNA-binding motif, they play distinct roles in renal fibrosis and inflammation during the development of DN as deletion of Smad3 suppresses, but deletion of Smad2 promotes, renal fibrosis in various mouse models of kidney diseases, including DN [50,51,52,53]. In vitro evidence also confirms this functional diversity, as Smad3—but not Smad2—mediates the fibrosis response induced by TGF-β1, high glucose, AGE, and Ang II [29, 31, 32, 50, 54, 55]. One recent study further demonstrated that deletion of Smad3 from db/db mice is capable of protecting db/db mice from the development of DN [56]. Compared with Smad3 wild-type db/db mice with severe diabetes and DN, age-matched Smad3-null db/db mice show normal levels of urinary albumin and serum creatinine without notable renal inflammation and fibrosis [56].

In contrast to the profibrotic role of Smad3, Smad2 plays an antifibrotic role as specific deletion of Smad2 in tubular cells using KSP-Cre promotes renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) [50]. However, Loeffler et al [57]. reported an antifibrosis phenotype in STZ-induced DN [56] by specific deletion of Smad2 in fibroblasts driven by fibroblast-specific protein 1 (FSP1)-Cre. This discrepancy may be attributed to the difference in the genetic mouse models used, implying the distinct roles of Smad2 in different cell types during fibrosis.

Smad7 is an inhibitory Smad that functions to counterbalance the activity of TGF-β signaling by suppressing the phosphorylation of R-Smads and inducing ubiquitin-mediated degradation of TGFBR1 [19, 20]. Deletion of Smad7 aggravates, but overexpression of Smad7 inhibits, renal fibrosis and inflammation in various animal models of kidney disease, including UUO, 5/6 nephrectomy, crescentic glomerulonephritis, aristolochic acid nephropathy, hypertensive nephropathy, and DN [32, 58,59,60,61,62,63,64,65,66,67,68,69]. In vitro overexpression of Smad7 in renal tubular cells and VSMCs suppresses fibrosis induced by TGF-β, high glucose, AGE, and Ang II [14, 32, 70, 71]. Mechanistically, the renal protective role of Smad7 is associated with inactivation of both TGF-β and NF-κB signaling [68, 69]. Indeed, as illustrated in Figure 1, overexpression of Smad7 not only inhibits TGF-β/Smad3-mediated renal fibrosis but also inactivates NF-κB signaling by inducing IκBα, thereby inhibiting renal inflammation [62, 72]. In addition, Smad7 is also responsible for the anti-inflammatory effect of TGF-β1, as TGF-β1 can induce the expression of Smad7 [62, 73]. Therefore, Smad7 has both antifibrotic and anti-inflammatory properties and may be a therapeutic agent for various kidney diseases, including DN [74].

Role of Smad3-Dependent Noncoding RNAs in DN

In the genome, >98% of genes are noncoding RNAs, with about 1.2% of genes producing proteins [75]. Noncoding RNAs can be classified into transfer RNAs (tRNAs), heterogeneous nuclear RNAs (hnRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and so on [75]. Among them, miRNAs and lncRNAs play pivotal regulatory roles in diverse biological and disease processes. Accumulating evidence indicates that TGF-β/Smad3 signaling regulates a number of miRNAs and lncRNAs to mediate DN (Figure 2).

Figure 2

TGF-β/Smad3-dependent miRNAs and lncRNAs in DN. Smad3 can transcriptionally induce miR-21, miR-192, miR-377, Erbb4-IR, LncRNA9884, and Arid2-IR but suppress the miR-29a/b and miR-200a families, contributing to the modulation of renal fibrosis and inflammation in DN. The red line indicates pathogenic, whereas green line implies protective, pathways. The arrow stands for positive regulation, and blunt line represents negative regulation. DN, diabetic nephropathy; lncRNA, long noncoding RNA; miRNA (miR), microRNA; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.

Role of Smad3-dependent miRNAs in DN

miRNAs are short noncoding RNAs that posttranscriptionally repress gene expression by binding to the 3′-untranslated region (UTR) of their target mRNAs to induce their degradation or translational suppression [76, 77]. Microarray-based screening and subsequent functional studies identified multiple miRNAs that are regulated by TGF-β signaling and that modulate the pathogenesis of kidney disease [76,77,78]. Among them, it is now clear that miR-21, miR-192, and miR-377 are pathogenic, whereas miR-29a/b and miR-200a are protective in DN.

miR-21 is a Smad3-dependent miRNA and plays a pathogenic role in the renal fibrosis of UUO mice [78]. miR-21 is also found to be upregulated in DN of db/db mice, while knockdown of miR-21 ameliorates DN by inhibiting renal fibrosis and inflammation. Mechanistically, miR-21 promotes renal fibrosis and inflammation in db/db mice by suppressing Smad7 by binding to its 3′-UTR [79]. miR-192 is another Smad3-dependent miRNA that shows increased expression in the glomeruli of db/db and STZ-induced diabetic mice [80, 81]. In vitro, silencing miR-192 blocks but overexpression of miR-192 promotes TGF-β1-induced production of ECM [81]. Further analysis revealed that miR-192 targets Smad-interacting protein 1 (SIP1), which is an E-box repressor, to suppress Col1a2 transcription [80]. Therefore, miR-192 mediates TGF-β/Smad3 signaling-driven fibrosis by promoting the collagen gene Col1a2 by decreasing SIP1. miR-377 is increased in STZ-induced DN and in TGF-β- or high glucose-stimulated MCs. miR-377 contributes to fibrosis by promoting fibronectin expression, although the detailed mechanism remains to be elucidated [82].

miR-29b is an antifibrotic miRNA which is expressed in fibrotic diseases of multiple organs, including the heart [83], liver [84], lung, and kidney [85, 86]. In DN, the expression of miR-29b is downregulated by AGE in a Smad3-dependent manner. Overexpression of miR-29b improves DN by attenuating fibrosis and inflammation [87]. Mechanistically, miR-29b suppresses TGF-β signaling by targeting the third exon of Tgfb1 mRNA in heart-derived fibroblasts [83]. In addition to miR-29b, another member of the miR-29 cluster, namely, miR-29a, is also downregulated by TGF-β1 and high glucose in vitro. miR-29a directly targets the 3′-UTR of the collagen genes Col4a1 and Col4a2 to suppress ECM production [88]. Similar to miR-29b, overexpression of miR-29a also shows a renoprotective effect on DN [89]. miR-200a is another miRNA that is downregulated in DN in response to TGF-β1 and TGF-β2 treatment, whereas overexpression of miR-200a attenuates TGF-β/Smad3 signaling and renal fibrosis. Further analysis indicates that miR-200a negatively regulates TGF-β signaling by binding to the 3′-UTR of Tgfb2 [90]. Ahn et al [91] identified a Smad3-binding site in the promoter of miR-200a/b. However, they found that Smad3 activates but does not suppress transcription of miR200a/b in gastric cancer cells. Therefore, Smad3 may regulate miR-200a expression in a cell type-dependent manner.

Role of Smad3-dependent lncRNAs in DN

Furthermore, lncRNAs are another group of noncoding RNAs of >200 nucleotides in length. Using RNA sequencing (RNA-Seq), thousands of lncRNAs have been discovered, many of which have been proven to play important roles in various biological processes with distinct mechanisms [92]. In tissue fibrosis, many lncRNAs are dysregulated by TGF-β signaling [93]. With respect to kidney disease, Zhou et al [94]. found 21 lncRNAs that are tightly regulated by TGF-β/Smad3 signaling in both UUO and anti-GBM glomerulonephritis mouse models. Further studies revealed that some of these lncRNAs execute critical roles in different kidney diseases, including DN. Among them, lncRNA Erbb4-IR (np_5318), which is localized in the intron of Erbb4 gene, is highly expressed in the UUO kidney and in DN in db/db mice [88, 89]. Silencing Erbb4-IR attenuates renal fibrosis in both mouse models of UUO and diabetic kidney diseases, as well as in TGF-β1- and AGE-treated tubular cells [95]. It is now clear that Erbb4-IR can be induced in a Smad3-dependent manner, which promotes renal fibrosis by binding to the genomic locus of miR-29b and the 5′-UTR of Smad7 to suppress their expression [95, 96]. Another lncRNA, LncRNA9884 (na_9884), is intensively upregulated in the nucleus of renal tubular cells and MCs of db/db mice and can also be stimulated in vitro by AGE and high glucose in a Smad3-dependent manner. Silencing LncRNA9884 protects against renal injury in db/db mice by alleviating mesangial expansion, glomerulosclerosis, albuminuria, and serum creatinine levels. Mechanistic studies have revealed that lncRNA9884 promotes inflammation by transcriptionally inducing monocyte chemoattractant protein (MCP)-1 by physically binding to its promoter [97]. In addition, in the UUO kidney, another Smad3-dependent lncRNA, Arid2-IR (np_28496), has been found to promote inflammation via the NF-κB-dependent mechanism [98]. However, the role of Arid2-IR in DN remains unclear.

Treatment of DN by Targeting TGF-b Signaling

Considering the pathogenic role of TGF-β signaling in DN, inhibition of this signaling pathway may represent a novel therapy for DN. This is supported by the findings that targeting the TGF-β/Smad signaling by antibody-mediated blockade of TGF-β ligand [44,45,46], genetic deletion of Tgfbr2 or downstream mediator Smad3 [49, 56, 67, 99], and overexpression of Smad7 [68, 69] are capable of alleviating renal injury in both type-1 and type-2 diabetic animal models. However, as TGF-β is also an anti-inflammatory cytokine and because Smad3-null mice develop impaired mucosal immunity, long-termed blockade of TGF-β/Smad signaling may cause unwanted side effects [62, 100]. Thus, treatment by targeting TGF-β/Smad signaling should be focused on rebalancing the downstream Smads by inactivating Smad3 while restoring Smad7 as Smad7 can inhibit both Smad3-driven fibrosis and NF-κB-signaling-driven inflammation in a number of disease models, including DN [74]. As illustrated in Figure 2, targeting the downstream Smad3-dependent miRNAs and lncRNAs may be another promising treatment strategy for DN. This can be achieved by silencing the pathogenic miR-21, miR-192, miR-377, Erbb4-IR, and LncRNA9884 or by overexpressing the beneficial miR-29a/b and miR-200a, as reported in a number of studies [79, 81, 82, 87, 88, 90, 96, 97].

Pharmaceutical inhibition of TGF-β signaling may be another promising therapeutic approach for DN. As shown in Table 1, oral delivery of GW788388, a phosphorylation inhibitor targeting both TGFBR1 and TGFBR2, decreases renal fibrosis and albuminuria in db/db mice [101]. In addition, a novel chemical, halofuginone, which shows notable inhibitory activity on TGF-β signaling by decreasing Smad2 phosphorylation and TGFBR2 expression, has an antifibrotic effect on DN in db/db mice [102]. Furthermore, directly targeting Smad3 with the Smad3 inhibitor SIS3 also inhibits renal injury in STZ-induced DN [103].

List of TGF-β signaling-targeting chemical agents with validated efficacy in the treatment of DN.

Chemical agent name Test model Function and underlying mechanism Reference
GW788388 db/db mice Decreases renal fibrosis and albuminuria by targeting phosphorylation of TGFBR1 and TGFBR2 [101]
Halofuginone db/db mice Attenuates glomerular mesangial expansion and interstitial fibrosis by inhibiting phosphorylation of Smad2 and transcription of Tgfbr2 [102]
SIS3 STZ-induced DN in mice Reduces renal fibrosis by suppressing endothelial–mesenchymal transition by targeting Smad3 phosphorylation [103]
Naringenin db/db mice Reduces renal fibrosis by functioning as a Smad3 inhibitor [104] and unpublished data
Asiatic acid db/db mice Reduces renal fibrosis by functioning as an agonist of Smad7 [104] and unpublished data

DN, diabetic nephropathy; STZ, streptozocin; TGF-b, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.

Increasing evidence shows that the use of traditional Chinese medicine (TCM) or herbal medicine could be an alternative preventive or therapeutic treatment for DN. TCM is considered to contain multiple active ingredients/compounds that target multiple mediators or pathways. TCM prescriptions have been widely used in clinical applications in many Asian countries with controllable side effects [105]. Large cohort-based retrospective analysis has proven that TCM improves the long-term survival of patients with chronic kidney disease [106]. TCM prescriptions Tangshen formula and Chaihuang-Yishen granule have been demonstrated to have plausible clinical efficacy in patients with DN [107,108,109]. Animal studies indicate that these two TCM prescriptions substantially inhibit TGF-β signaling and renal fibrosis, with improvement of renal function, in DN [107,108,109]. In addition, a number of compounds extracted from plants, such as berberine (an isoquinoline alkaloid from Cortex Phellodendri Chinensis), asiatic acid (a triterpenoid from Centella asiatica), and naringenin (a flavonoid found abundantly in citrus) also show ability to lower blood glucose, improve metabolic abnormalities–especially insulin insensitivity and glucose tolerance, and decrease renal fibrosis and inflammation in db/db mice [104, 110]. Mechanistically, naringenin has been found to act as a Smad3 inhibitor, while asiatic acid functions as a Smad7 agonist. The combination of naringenin and asiatic acid can effectively rebalance Smad3/Smad7 signaling and therefore synergistically attenuate progressive renal fibrosis and inflammation [104, 111]. Clinical trials to validate the therapeutic efficacy of these herbal extracts on chronic kidney diseases, including DN, are warranted.

Conclusion

TGF-β signaling is a major pathway leading to the development of DN. TGF-β signaling can be activated and dysregulated by many diabetic mediators, including high glucose, AGE, Ang II, free fatty acid, and CRP, through TGF-β-dependent and -independent mechanisms. Generally, Smad3 is pathogenic and highly activated, while Smad7 is protective but downregulated, during the pathogenesis of DN. Thus, treatment by rebalancing Smad3/Smad7 signaling could be a better preventive and therapeutic strategy for combatting DN. In addition, Smad3 may mediate DN by transcriptionally upregulating the pathogenic, while inhibiting the renoprotective, miRNAs/lncRNAs, which may also be specific targets for the treatment of DN. Development of pharmaceutical inhibitors or TCM compounds that directly target or balance Smad3/Smad7 signaling could be a better approach for the prevention and treatment of DN.

Figure 1

Regulatory pathways of TGF-β signaling in DN. Smad2/3 can be activated by both TGF-β-dependent and -independent mechanisms. Many stress molecules such as Ang II, AGE, and CRP can activate Smad2/3 to exert their biological effects via cross talk with ERK/p38 MAPK pathway. High glucose promotes the activation of latent TGF-β ligand and the transcription of Tgfb1 and Tgfbr2. In addition, Smad7 functions to counteract Smad2/3 signaling via the negative feedback loop and suppresses NF-κB activation by inducing IκBα. The red line indicates pathogenic, whereas the green line implies protective, pathways. The arrow stands for positive regulation, and the blunt line represents negative regulation. AGE, advanced glycation end product; Ang II, angiotensin II; AT1/2, Ang II type 1/2 receptor; CD, cluster of differentiation; CRP, C-reactive protein; DN, diabetic nephropathy; Erk, extracellular signal-regulated kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; RAGE, receptor of AGE; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.
Regulatory pathways of TGF-β signaling in DN. Smad2/3 can be activated by both TGF-β-dependent and -independent mechanisms. Many stress molecules such as Ang II, AGE, and CRP can activate Smad2/3 to exert their biological effects via cross talk with ERK/p38 MAPK pathway. High glucose promotes the activation of latent TGF-β ligand and the transcription of Tgfb1 and Tgfbr2. In addition, Smad7 functions to counteract Smad2/3 signaling via the negative feedback loop and suppresses NF-κB activation by inducing IκBα. The red line indicates pathogenic, whereas the green line implies protective, pathways. The arrow stands for positive regulation, and the blunt line represents negative regulation. AGE, advanced glycation end product; Ang II, angiotensin II; AT1/2, Ang II type 1/2 receptor; CD, cluster of differentiation; CRP, C-reactive protein; DN, diabetic nephropathy; Erk, extracellular signal-regulated kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; RAGE, receptor of AGE; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.

Figure 2

TGF-β/Smad3-dependent miRNAs and lncRNAs in DN. Smad3 can transcriptionally induce miR-21, miR-192, miR-377, Erbb4-IR, LncRNA9884, and Arid2-IR but suppress the miR-29a/b and miR-200a families, contributing to the modulation of renal fibrosis and inflammation in DN. The red line indicates pathogenic, whereas green line implies protective, pathways. The arrow stands for positive regulation, and blunt line represents negative regulation. DN, diabetic nephropathy; lncRNA, long noncoding RNA; miRNA (miR), microRNA; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.
TGF-β/Smad3-dependent miRNAs and lncRNAs in DN. Smad3 can transcriptionally induce miR-21, miR-192, miR-377, Erbb4-IR, LncRNA9884, and Arid2-IR but suppress the miR-29a/b and miR-200a families, contributing to the modulation of renal fibrosis and inflammation in DN. The red line indicates pathogenic, whereas green line implies protective, pathways. The arrow stands for positive regulation, and blunt line represents negative regulation. DN, diabetic nephropathy; lncRNA, long noncoding RNA; miRNA (miR), microRNA; TGF-β, transforming growth factor beta; TGFBR, transforming growth factor beta receptor.

List of TGF-β signaling-targeting chemical agents with validated efficacy in the treatment of DN.

Chemical agent name Test model Function and underlying mechanism Reference
GW788388 db/db mice Decreases renal fibrosis and albuminuria by targeting phosphorylation of TGFBR1 and TGFBR2 [101]
Halofuginone db/db mice Attenuates glomerular mesangial expansion and interstitial fibrosis by inhibiting phosphorylation of Smad2 and transcription of Tgfbr2 [102]
SIS3 STZ-induced DN in mice Reduces renal fibrosis by suppressing endothelial–mesenchymal transition by targeting Smad3 phosphorylation [103]
Naringenin db/db mice Reduces renal fibrosis by functioning as a Smad3 inhibitor [104] and unpublished data
Asiatic acid db/db mice Reduces renal fibrosis by functioning as an agonist of Smad7 [104] and unpublished data

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