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| EDITORIAL |
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| Year : 2021 | Volume
: 8
| Issue : 1 | Page : 1 |
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The yin and yang role of transforming growth factor-β in kidney disease
Hui-yao Lan
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong; The CUHK-Guangdong Provential People's Hospital Joint Laboratory for Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong, China
| Date of Submission | 12-Mar-2021 |
| Date of Decision | 09-Jun-2021 |
| Date of Acceptance | 22-Jul-2021 |
| Date of Web Publication | 08-Sep-2021 |
Correspondence Address:
Dr. Hui-yao Lan
Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/imna.imna_17_21
How to cite this article:
Lan Hy. The yin and yang role of transforming growth factor-β in kidney disease
. Integr Med Nephrol Androl 2021;8:1 |
Transforming growth factor-β (TGF-β) is a founding member of the TGF-β superfamily including activins, inhibins, growth and differentiation factors, and bone morphogenetic proteins. TGF-β and its isoforms (TGF-β2 and TGF-β3) are synthesized and secreted as latent precursors (latent TGF-β1) complexed with latent TGF-β-binding proteins (LTBP) and become active when TGF-β is liberated from the latency-associated peptide and dissociated from LTBP through proteolytic cleavage mechanisms. Active TGF-β then binds its receptors and functions as autocrine and paracrine manners to exert its biological and pathological activities through Smad-dependent and independent signaling pathways.[1] Of them, the Smad signaling pathway has been well studied and considered to be a major pathway driving the pathophysiological process of kidney disease.[1],[2] After binding to its receptors, TGF-β can activate two receptor-associated Smads including Smad2 and Smad3 by phosphorylation, which subsequentially binds to the common Smad4 to form the Smad complex and translocate into the nucleus to regulate the target gene transcription including Smad7. Smad7 is an inhibitory Smad that inhibits Smad2 and Smad3 activation by targeting the TβRI and Smad proteins for degradation through the Smurf2 and Arkidia ubiquitin proteasome degradation mechanisms.[1]
TGF-β, like the Chinese Yin and Yang philosophy, exerts its diverse roles in kidney disease including acute kidney injury (AKI) and chronic kidney disease (CKD).[3] It has been well documented that TGF-β is a key mediator in renal fibrosis, whereas TGF-β is also a potent anti-inflammatory cytokine that plays a protective role in renal inflammation.[3],[4],[5] There are distinct roles for latent versus active TGF-β in kidney disease as mice overexpressing the active TGF-β1 result in progressive renal fibrosis, whereas, mice overexpressing latent TGF-β1 in the skin are protected against progressive renal inflammation and fibrosis in obstructive and immunologically induced crescentic glomerulonephritis.[3],[4] Thus, targeting TGF-β with neutralizing antibodies may inhibit renal fibrosis but promotes renal inflammation.[3],[4],[5] In addition, TGF-β is also an immune regulator in kidney disease and plays a diverse role in kidney disease as TGF-β1 can induce immunotolerance through a Foxp3-dependent Treg mechanism, while promoting Th-17 response by activating RORγt signaling.[6]
Again, TGF-β1 can signal through its downstream Smad signaling molecules to Yin and Yang regulate renal fibrosis and inflammation in the progression of AKI-to-CKD.[1],[2],[7] In the context of renal fibrosis and inflammation, Smad3 is pathogenic as genetically deletion of Smad3 or pharmacological blockade of Smad3 can inhibit renal inflammation and fibrosis in mouse models of obstructive, hypertensive, and diabetic nephropathy.[1],[2],[7] In contrast, Smad2 and Smad7 are protective because mice lacking Smad2 and Smad7 are promoted Smad3-dependent renal fibrosis in these kidney disease models. Whereas, Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting nuclear factor kappa B (NF-κB)-driven renal inflammation through a Smad7-dependent mechanism.[1],[2],[3],[7] Strikingly, our recent studies also revealed a driving role for TGF-β/Smad3 in the inflammation-to-fibrosis process through a novel mechanism of macrophage-to-myofibroblast transition,[8] in addition to the known role of TGF-beta signaling in epithelial–mesenchymal transition and endothelial–mesenchymal transition.[9] Moreover, we also found that Smad3 is pathogenic in AKI by causing tubular epithelial cell death through the G1 cell cycle arrest mechanism, which can be blocked by genetically deletion of Smad3 or by a Smad3 inhibitor.[10] In contrast, Smad7 is protective as mice lacking Smad7 develop much more severe AKI.
TGF-β1 also acts through Smad-dependent and independent signaling pathways to positively or negatively regulate renal inflammation and fibrosis through noncoding RNA (ncRNAs) including microRNAs (miRNAs) and long ncRNAs (lncRNAs)-dependent mechanisms.[1],[2],[7] TGF-β can activate Smad3 to causes renal fibrosis by upregulating miR-21, miR-192, and miR-433, while downregulating miR-29 and miR-200 family.[1],[2],[7] TGF-β also induces renal inflammation and fibrosis by increasing renal lncRNA Arid2-IR, Erbb4-IR, and LRNA9884, while suppressing taurine upregulated gene 1 (TUG1) and TGF-β/Smad3-interacting lncRNA (lnc-TSI) through a Smad3-dependent mechanism.[1],[2],[7] Moreover, Smad3 can also induce miRNAs and lncRNAs to specifically target Smad7.[3] For example, TGF-β1 can induce the activation of Smad3 to upregulate miR-21, which binds to the 3' UTR of Smad7 and inhibits its translation.[2],[7] Similarly, Smad3 can also induce lncRNA Erbb4-IR to cause progressive renal fibrosis by directly targeting Smad7. In contrast, overexpression of Smad7 inhibits renal inflammation and fibrosis by counter-regulating Smad3-dependent miRNAs/lncRNAs.[2],[7] All these findings also reveal the Yin and Yang role for TGF-β signaling in renal inflammation and fibrosis through the downstream ncRNA-dependent mechanisms.
Although TGF-β has been considered as a key mediator in fibrogenesis, treatment of kidney disease by generally targeting TGF-β has been controversial. In fact, blockade of upstream TGF-β signaling may not be a good strategy for the treatment of kidney disease due to its diverse role in renal inflammation and fibrosis.[3],[4],[5] It has been shown that general blockade of TGF-β signaling may attenuate renal fibrosis but also causes renal inflammation.[3],[4] This may well explain the failure of two recent clinical trials, in which treatment with anti-TGF-β antibodies (LY2382770 or Fresolimumab) on patients with diabetic nephropathy and focal segmental glomerulosclerosis has shown nonbeneficial effective clinically.[3],[4] Thus, treatment for kidney disease should target the downstream TGF-β signaling by either inhibiting Smad3 or Smad3-dependent miRNAs/lncRNAs that specifically regulate renal inflammation or fibrosis or by overexpressing Smad7, rather than to block the general effect of TGF-β signaling. It has been reported that pharmacological inhibition or silencing of Smad3 or Smad3-dependent miRNAs (miR-21, miR-192, and miR-433) or lncRNAs (Erbb4-IR, Arid2-IR, and LRNA9884) is capable of attenuating renal inflammation and fibrosis in a number of animal models including obstructive and diabetic kidney diseases. In contrast, overexpression of miR-29, miR-200, TUG1, and Inc-TSI can inhibit Smad3-mediated renal fibrosis.[1],[2],[7] It should be noted that, although the rapid development of ncRNAs has implicated the RNA-based biopharmaceuticals to enter clinical trials, the clinical application of ncRNA treatments for kidney diseases remain limited, which is largely due to the low expression, low conservation between species, time specificity, toxicity, and off-target effects of ncRNAs. Nevertheless, ncRNA-based therapies may be the potential next-generation medicine for AKI and CKD. For example, a miR-29 mimic Remlarsen is undergoing in the clinical test (https://clinicaltrials.gov/ct2/show/NCT03601052) and could be the promising drug to combat renal fibrosis.
In conclusion, TGF-β/Smad signaling is a major pathway leading to AKI and CKD. TGF-β1 exerts its Yin or Yang role to diversely regulate renal inflammation and fibrosis. In the context of renal inflammation and fibrosis, latent TGF-β1 is protective, whereas active form of TGF-β1 is pathogenic. Among the downstream Smad signaling, Smad3 is pathogenic, whereas Smad2 and Smad7 are protective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Smad3 may mediate renal inflammation and fibrosis in AKI and CKD by directly targeting the downstream genes including miRNAs/lncRNAs transcriptionally, whereas Smad7 may inhibit renal inflammation and fibrosis by counter-regulating both TGF-β/Smad3 and NF-kB signaling. It is noted that TGF-β/Smad3 and Smad7 signaling is unbalancing in AKI and CKD, mostly with Smad3 overreactive while losing Smad7. Thus, rebalancing Smad3/Smad7 signaling by inhibiting Smad3 or Smad3-dependent miRNAs/lncRNAs that specifically relate to renal inflammation and fibrosis or by overexpressing Smad7 may be good therapeutic strategies for AKI and CKD.[1],[2],[3],[7],[9] Treatment with Traditional Chinese Medicine by balancing the Yin and Yang role of TGF-β could be another good therapeutic strategy for kidney disease. As we previously described,[3] Naringenin from fruits is a Smad3 inhibitor and Asiatic acid derived from Centella asiatica functions as a Smad7 agonist and the combinational use is able to effetely restore the balance of Smad3/Smad7 signaling and thus additively inhibits renal fibrosis in rodent obstructive nephropathy. Similarly, the combination of Ginsenoside Rg1 and Astragaloside IV is also able to improve renal fibrosis and inflammation in STZ-induced diabetic nephropathy by rebalancing TGF-β/Smad2/3 and Smad7 signaling. It may also be true that targeting TGF-β signaling could be a novel therapeutic strategy for COVID-19-associated AKI as TGF-β signaling is overreactive in COVID-19 patients with AKI.[11]
Source of Funding
This work is supported by the Research Grants Council of Hong Kong ((14117418, 14104019, 14101121, R4012-18); the Health and Medical Research Fund of Hong Kong (05161326, 14152321, 07180516); and the Guangdong-Hong Kong-Macao Joint Labs Program from Guangdong Science and Technology (2019B121205005).
| References | |  |
| 1. | Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: The master regulator of fibrosis. Nat Rev Nephrol 2016;12:325-38.  |
| 2. | Tang PM, Zhang YY, Mak TS, Tang PC, Huang XR, Lan HY. Transforming growth factor-β signalling in renal fibrosis: From Smads to non-coding RNAs. J Physiol 2018;596:3493-503. |
| 3. | Gu YY, Liu XS, Huang XR, Yu XQ, Lan HY. Diverse role of TGF-β in kidney disease. Front Cell Dev Biol 2020;8:123. |
| 4. | Gewin L. The many talents of transforming growth factor-β in the kidney. Curr Opin Nephrol Hypertens 2019;28:203-10. |
| 5. | Sureshbabu A, Muhsin SA, Choi ME. TGF-β signaling in the kidney: Profibrotic and protective effects. Am J Physiol Renal Physiol 2016;310:F596-606. |
| 6. | Li MO, Flavell RA. TGF-beta: A master of all T cell trades. Cell 2008;134:392-404. |
| 7. | Gu YY, Lu FH, Huang XR, Zhang L, Mao W, Yu XQ, et al. Non-coding RNAs as biomarkers and therapeutic targets for diabetic kidney disease. Front Pharmacol 2020;11:583528. |
| 8. | Tang PM, Nikolic-Paterson DJ, Lan HY. Macrophages: Versatile players in renal inflammation and fibrosis. Nat Rev Nephrol 2019;15:144-58. |
| 9. | Srivastava SP, Hedayat AF, Kanasaki K, Goodwin JE. microrna crosstalk influences epithelial-to-mesenchymal, endothelial-to-mesenchymal, and macrophage-to-mesenchymal transitions in the kidney. Front Pharmacol 2019;10:904. |
| 10. | Lai W, Tang Y, Huang XR, Ming-Kuen Tang P, Xu A, Szalai AJ, et al. C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E. Kidney Int 2016;90:610-26. |
| 11. | Gu YY, Zhang M, Cen H, Wu YF, Lu Z, Lu F, et al. Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study. PLoS One 2021;16:e0245209. |
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