Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Abstract

Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Many components contribute to EMT through the TGF‐β1 signaling pathway, which indicates that the inhibition of the TGF‐β1 signaling pathway may be effective in the treatment of cancer and fibrosis. Several excellent reviews have discussed the role of the TGF‐β1 signaling pathway in tumors and fibrosis well . Here, we present several important small molecules that suppress EMT in tumors and fibrosis by targeting the TGF‐β1 signaling pathway (Table ).…”

“…TGF-β1 plays a crucial role in various cellular functions, including cell growth, proliferation, differentiation, and apoptosis, and is considered a key mediator in EMT during the processes of tumor formation and fibrosis. 117 Many components contribute to EMT through the TGF-β1 signaling pathway, which indicates that the inhibition of the TGF-β1 signaling pathway may be effective in the treatment of cancer and fibrosis. Several excellent reviews have discussed the role of the TGF-β1 signaling pathway in tumors and fibrosis well.…”

“…Several excellent reviews have discussed the role of the TGF-β1 signaling pathway in tumors and fibrosis well. 117,118 Here, we present several important small molecules that suppress EMT in tumors and fibrosis by targeting the TGF-β1 signaling pathway (Table 1).…”

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

“…Moreover, NOS3 and NOS2-although not associated with CKD in OMIM -have already been implicated in Chronic Kidney Disease in a fair amount of studies 24, 25,26,27 , while MEF2C, a gene typically associated with mental disorders, has also been associated with estimated Glomerular Filtration Rate (eGFR) or proteinuria 28 . SCLT1 deficiency has been linked with cystic kidney 29 and SMAD genes (including SMAD3) have been reported to affect CKD progression when dysregulated 30 . INPP5B impairment has been associated with severe renal phenotypes, such as proximal tubule endocytosis 31 , while targeting NFE2L2 (NRF2) has been tested for prevention of Kidney Disease Progression 32 .…”

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

“…Lineage tracing suggests that these disease-causative cells arise predominantly from glioma-associated oncogene homolog 1 + -forkhead box (FOX) D1 + vascular pericytes and fibroblasts (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), a conclusion supported by sine oculis homeobox homolog 2 fate mapping of the injured renal epithelium (35,37). TGF-b1 governs the myofibroblastic differentiation of pericytes and resident fibroblasts while coordinating a program of pathologic ECM synthesis and advancing fibrosis (38)(39)(40)(41)(42)(43)(44). Indeed, mice engineered to express epithelial-targeted, inducible, constitutively active TGF-b receptor I exhibit acute tubular injury and apoptosis, phenotypic dedifferentiation, synthesis of profibrotic factors, and interstitial inflammatory cell recruitment (45).…”