Disruption of Smad7 Promotes ANG II-Mediated Renal Inflammation and Fibrosis via Sp1-TGF-β/Smad3-NF.κB-Dependent Mechanisms in Mice

Abstract

Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p<0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-β/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1β and TNF-α expression, and a marked activation of NF-κB signaling (all p<0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-β1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. Thus, Smad7 may play a protective role in ANG II-induced hypertensive kidney disease.

The Effects of Leptin Administration on Renal Function in Spontaneously Hypertensive Rats

“…TGF-β1 expression was also higher, along with changes in mesangium and glomerular basement membrane, in db/db mice similar to changes seen in nephropathy of Type 2 diabetes mellitus [20]. Similar evidence has also been reported from human studies where increased TGF-β1 is associated with a higher risk for liver cirrhosis [21,22]. TGF-β1 effects are mediated through TGF-β1 Type II receptors and the Smad pathway.…”

“…The exact mechanism responsible for leptinstimulated increase in TGF-β1 expression is unclear, but evidence from studies on nonalcoholic steatohepatitis suggests that leptin-mediated oxidative stress might be responsible for the elevated TGF-β1 levels [23]. Decreased Smad7 might be associated with increased renal fibrosis as Smad7 knockout mice been found to show a more severe progression of renal dysfunction and renal fibrosis than wild-type control animals, suggesting a protective role for Smad7 in renal fibrosis [21]. BMP7 activation occurs by pathways independent of TGF-β1, and it is possible leptin administration simultaneously triggered BMP7 expression.…”

Smad7 regulates terminal maturation of chondrocytes in the growth plate

“…We chose to use this allele because it is well characterized structurally and phenotypically (e.g. (Li et al, 2006a; Liu et al, 2013; Wang et al, 2013). Smad7−/− embryos were recovered in Mendelian ratios up to E18.5.…”

Molecular Mechanisms of TGF-β Signaling in Renal Fibrosis

“…Thus, this aberrant expression of Smad7 results in enhancing further activation of TGF-b/Smad signaling and progressive renal fibrosis as evidenced in various rodent models of kidney diseases [35, 36, 64, 67 • , 68]. This is further confirmed in Smad7 KO mice in UUO, diabetic, and hypertensive models in which more severe renal fibrosis is developed [35, 43,69].…”