TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Nickel oxide nanoparticles (Nano NiO) bears hepatotoxicity, while whether it leads to liver fibrosis remains unclear. The aim of this study was to establish the Nano NiO‐induced hepatic fibrosis model in vivo and investigate the roles of transforming growth factor β1 (TGF‐β1) in Smad pathway activation, epithelial‐mesenchymal transition (EMT) occurrence, and extracellular matrix (ECM) deposition in vitro. Male Wistar rats were exposed to 0.015, 0.06, and 0.24 mg/kg Nano NiO by intratracheal instilling twice a week for 9 weeks. HepG2 cells were treated with 100 μg/mL Nano NiO and TGF‐β1 inhibitor (SB431542) to explore the mechanism of collagen formation. Results of Masson staining as well as the elevated levels of type I collagen (Col‐I) and Col‐III suggested that Nano NiO resulted in hepatic fibrosis in rats. Furthermore, Nano NiO increased the protein expression of TGF‐β1, p‐Smad2, p‐Smad3, alpha‐smooth muscle actin (α‐SMA), matrix metalloproteinase9 (MMP9), and tissue inhibitors of metalloproteinase1 (TIMP1), while decreased the protein content of E‐cadherin and Smad7 in rat liver and HepG2 cells. Most importantly, Nano NiO‐triggered the abnormal expression of the abovementioned proteins were all alleviated by co‐treatment with SB431542, implying that TGF‐β1‐mediated Smad pathway, EMT and MMP9/TIMP1 imbalance were involved in overproduction of collagen in HepG2 cells. In conclusion, these findings indicated that Nano NiO induced hepatic fibrosis via TGF‐β1‐mediated Smad pathway activation, EMT occurrence, and ECM deposition.     

Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol‐induced cardiac remodelling in mice through TGF‐β1/Smad3 pathway

It is well‐accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of α7 nicotinic acetylcholine receptor (α7nAChR) causes an anti‐inflammatory effect, the role of α7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific α7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross‐sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP‐9), transforming growth factor β1 (TGF‐β1), and Smad3 were analyzed by Western blot. ISO‐induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP‐9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF‐β1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF‐β1/Smad3 pathway. These data imply that the α7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases.     

Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney

Cyclophilin D (CypD) is an important component in mitochondrial‐dependent tubular cell death in acute kidney injury. However, it is not known whether CypD contributes to tubular cell damage in chronic interstitial fibrosis. We investigated this question in the unilateral ureter obstruction (UUO) model of renal interstitial fibrosis. Groups of CypD^?/? and wild type (WT) mice were killed 7 or 12 days after UUO surgery. The significant tubular cell apoptosis seen in WT UUO was significantly reduced in CypD^?/? UUO based on TUNEL and cleaved caspase 3 staining. Other markers of tubular cell damage; loss of E‐cadherin and AQP1 expression, were also reduced in the CypD^?/? UUO kidney. This reduced tubular damage was associated with less inflammation and a partial protection against loss of peritubular capillaries. The prominent accumulation of α‐SMA+ myofibroblasts and interstitial collagen deposition seen in WT UUO was significantly reduced in CypD^?/? UUO on day 12, but not day 7. Activation of several pro‐fibrotic signalling pathways (p38 MAPK, JNK and Smad3) was unaltered in CypD^?/? UUO, arguing that CypD acts independently to promote renal fibrosis. CypD deletion in cultured tubular cells attenuated oxidative stress‐induced pro‐inflammatory, pro‐fibrotic and apoptotic responses; however, responses to angiotensin II and LPS were unaffected. In contrast, CypD deletion in cultured renal fibroblasts did not affect PDGF‐induced proliferation or TGF‐β1‐induced collagen I expression, suggesting no direct role of CypD in the fibroblast response. In conclusion, we have identified a role for CypD in chronic tubular cell damage and in the development of renal interstitial fibrosis.     

Glycyrrhizin regulates CD4+T cell response during liver fibrogenesis via JNK,ERK and PI3K/AKT pathway

The aims of this study were to elucidate the immunomodulatory effects of glycyrrhizin (GL) on CD4⁺T cell responses during liver fibrogenesis. To obtain in vivo evidence about the effects of GL on CD4⁺T cells in livers and spleens of concanavalin A (ConA)-induced mouse model, mice were administrated with ConA together with or without GL for 8 weeks. Mice treated with GL dramatically prevented liver inflammation and fibrosis. Besides, GL inhibited the infiltration of T helper (Th) cell type 1, Th2, Th17 and regulatory T cells (Treg) in livers and spleens of mouse fibrosis models, and regulated the Th1/Th2 and Treg/Th17 balances respectively to a relative dominance of Th1 and Treg lineages in livers. Moreover, GL dramatically enhanced the antifibrotic cytokine interferon (IFN)‐γ and interleukin (IL)-10. GL at a concentration of 10 or 100 μg/mL was respectively incubated with ConA-stimulated splenic CD4⁺T cells in vitro, and JNK inhibitor (SP600125), ERK inhibitor (U0126), p38 inhibitor (SB203580) or PI3K/AKT inhibitor (LY29400225) was added during the incubation. Notably, GL not only inhibited ConA-induced proliferation of splenic CD4⁺T cells but also enhanced the mRNAs of IFN-γ and IL-10 in these cells. Be similar to the effects of GL, SP600125, U0126 and LY29400225, however not SB203580, also inhibited ConA-induced CD4⁺T cell proliferation, indicating the involvement of JNK, ERK and PI3K/AKT in this process. Moreover, GL significantly inhibited ConA-induced phosphorylation of JNK, ERK and PI3K/AKT in vitro. Collectively, GL might alleviate liver injury and fibrosis progression via regulation of CD4⁺T cell response in JNK, ERK and PI3K/AKT-dependent pathways.     

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial

Objectives Oltipraz, a cancer chemopreventive agent, has an anticirrhotic effect in animals. A phase II trial was designed to investigate the preliminary efficacy of oltipraz therapy in liver fibrosis or cirrhosis. Methods Of 83 patients who were randomized to receive placebo, oltipraz 60 mg bid or oltipraz 90 mg qd for 24 weeks, 68 completed the study without any major protocol violation. Pre‐ and post‐treatment liver biopsies, and blood fibrosis markers were assessed. Key findings Twenty‐four weeks of oltipraz treatment showed no significant differences in the proportions of patients showing an improvement in histological outcomes, including Ishak fibrosis score. In the oltipraz 60 mg bid group, there was a trend of decreases in hepatic collagen area and plasma transforming growth factor‐β1 (TGF‐β1, a blood fibrosis marker) levels from baseline to week 24. In the per‐protocol population (n = 68), decreases in plasma TGF‐β1 correlated with those in the Ishak fibrosis score, suggesting that circulating TGF‐β1 serves a possible indicator for fibrosis treatment. Conclusions No significant differences in liver histological outcomes were seen among the three treatment groups in this 24‐week pilot study. Our finding indicates an association between TGF‐β1 repression and improvement in the histological index of fibrosis.     

Effects of magnolol on vascular contraction in rat aortic rings

1. Magnolol (5,5′‐diallyl‐2,2′‐dihydroxybiphenyl) is a major phenolic compound purified from Magnolia officinalis. The aim of the present study was to elucidate the effects of magnolol on vascular contractions. 2. Rat aortic rings were mounted in organ baths. Magnolol was added cumulatively (0.3–30 μmol/L) to elicit relaxation in endothelium‐intact and ‐denuded rat aortic rings precontracted with U46619 (30 nmol/L, 20 min), NaF (8.0 mmol/L, 40 min), phenylephrine (1.0 or 0.1 μmol/L, 15 min) or phorbol‐12,13‐dibutyrate (PDBu, 0.3 or 0.1 μmol/L, 40 min). In separate experiments, cumulative concentration?response curves were obtained for NaF (2.0–12 mmol/L), U46619 (1.0 nmol/L?1.0 μmol/L) or PDBu (1.0 nmol/L?1.0 μmol/L) after pretreatment with either magnolol or vehicle for 30 min in endothelium‐denuded aortic rings. After completion of the functional study, we measured the amount of guanosine triphosphate (GTP) RhoA by using a G‐LISA RhoA Activation Assay, as well as the phosphorylation of 20 kDa myosin light chain (MLC₂₀), myosin phosphatase‐targeting subunit 1 (MYPT1) and protein kinase C‐potentiated inhibitory protein for heterotrimeric myosin light‐chain phosphatase of 17 kDa (CPI‐17) by immunobloting. 3. Magnolol (0.3–30 μmol/L) reduced vascular tension induced by the thromboxane A₂ agonist U46619 (30 nmol/L), sodium fluoride (NaF) (8.0 mmol/L) and the α₁‐adrenoceptor agonist phenylephrine (1.0 or 0.1 μmol/L) in both endothelium‐intact and ‐denuded rings. The magnitude of the relaxation effects of magnolol on the contraction induced by each of the drugs were similar. The magnitude of the effect of magnolol in endothelium‐intact and ‐denuded rings were similar. 4. Pretreatment of rat aortic rings with 1.0, 3.0 or 10 μmol/L magnolol for 30 min dose‐dependently inhibited the maximum response on the concentration–response curves to NaF and U46619, but not to phorbol‐12,13‐dibutyrate (PDBu). 5. Magnolol (3.0 or 10 μmol/L) decreased RhoA activation, as well as the phosphorylation of MLC₂₀, MYPT1_Thr855 and CPI‐17_Thr38 induced by either 8.0 mmol/L NaF or 30 nmol/L U46619. In contrast, magnolol did not affect PDBu (0.1 μmol/L)‐induced phosphorylation of CPI‐17_Thr38. 6. In conclusion, magnolol reduces vascular contraction by inhibiting the RhoA/Rho kinase pathway in endothelium‐denuded rat aorta.     

Potential protective effects of a traditional Chinese herb,Litsea coreana Levl., on liver fibrosis in rats

Objectives It was found that total flavonoids from Litsea coreana Levl. (TFLC), which is a traditional Chinese medicine, had a preventive effect against hepatic steatosis in our previous study. This study was designed to evaluate whether TFLC could improve liver fibrosis in rats. Methods The liver fibrosis model rats were treated with composite factors of high‐fat emulsion (10 ml/kg) via gavage accompanied by a subcutaneous injection of low‐dose CCl₄. Thirty rats were given composite factors plus TFLC (100, 200, 400 mg/kg), respectively, for 8 weeks. Key findings The results showed that TFLC (200 and 400 mg/kg) treatment significantly reduced the elevation of liver index (liver weight/body weight) and spleen index (spleen weight/body weight), alanine transaminase, aspartate aminotransferase, hyaluronic acid, laminin, procollagen III N‐terminal peptide, procollagenase IV and hydroxyproline. In addition, TFLC treatment improved the morphologic changes of hepatic fibrosis, suppressed expression of α‐smooth muscle actin, collagen I, transforming growth factor (TGF)‐β1 and TGFβ receptor (TGFβR)1, and increased peroxisome proliferator‐activated receptor‐γ expression in the liver of hepatic fibrosis rats. Conclusions In conclusion, TFLC is able to ameliorate liver injury and protect rats from liver fibrosis. This process may be related to inhibiting the expression of transforming growth factor‐β1 and increasing the expression of peroxisome proliferator‐activated receptor‐γ.     

Toll‐like receptor‐4 signalling in the progression of non‐alcoholic fatty liver disease induced by high‐fat and high‐fructose diet in mice

The aim of the present study was to investigate Toll‐like receptor‐4 (TLR4) signalling at different stages of non‐alcoholic fatty liver disease (NAFLD) induced by a high‐fat, high‐fructose (HFHFr) diet in mice. Both TLR4 wild‐type (WT) and mutant (TLR4^mut) mice were fed either standard chow (SC) or the HFHFr diet for different periods of time from 4 to 16 weeks. Pathological characteristics and function of the liver were assessed. Simple steatosis, steatohepatitis and hepatic fibrosis occurred sequentially in Week 4, 8 and 16 in WT mice fed with the HFHFr. Expression of TLR4, myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and IRF7 started to increase at Week 4, peaked at Week 8 and then declined to basal levels at Week 16. This pattern was consistent with changes in inflammation in the liver revealed by haematoxylin and eosin staining. However, lipid accumulation, inflammation and fibrosis in livers of TLR4^mut mice fed the HFHFr diet were significantly alleviated. In addition, the expression of activin A in WT mice fed the HFHFr diet increased at Week 16. The data suggest that TLR4 signalling mediates non‐alcoholic steatohepatitis before fibrosis and that activin A is subsequently involved in NAFLD.     

Lanatoside C protects mice against bleomycin‐induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

It has been established that lanatoside C, a FDA‐approved cardiac glycoside, reduces proliferation of cancer cell lines. The proliferation of fibroblasts is critical to the pathogenesis of pulmonary fibrosis (PF), a progressive and fatal fibrotic lung disease lacking effective treatment. In this study we have investigated the impact of lanatoside C on a bleomycin (BLM)‐induced mouse model of PF and through the evaluation of fibroblast proliferation and activation in vitro. We evaluated explanted lung tissue by histological staining, western blot analysis, qRT‐PCR and survival analysis, demonstrating that lanatoside C was able to protect mice against BLM‐induced pulmonary fibrosis. The proliferation of cultured pulmonary fibroblasts isolated from BLM‐induced PF mice was suppressed by lanatoside C, as hypothesized, through the induction of cell apoptosis and cell cycle arrest at the G2/M phase. The Akt signalling pathway was involved in this process. Interestingly, the production of α‐SMA, fibronectin, and collagen I and III in response to TGF‐β1 in healthy mouse fibroblasts was suppressed following lanatoside C administration by inhibition of TGF‐β1/Smad signalling. In addition, TGF‐β1‐induced migration in lung fibroblasts was also impeded after lanatoside C treatment. Together, our data revealed that lanatoside C alleviated BLM‐induced pulmonary fibrosis in mice via attenuation of growth and differentiation of fibroblasts, suggesting that it has potential as a candidate therapy for PF patients.     

Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl₄ for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl₄‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.     

Stevioside inhibits experimental fibrosis by down‐regulating profibrotic Smad pathways and blocking hepatic stellate cell activation

Liver cirrhosis is associated with increased morbidity and mortality with important health and social consequences; however, an effective treatment has not been found yet. Previous reports have shown some beneficial effects of stevioside (SVT) in different diseases, but the ability of SVT to inhibit liver cirrhosis has not been reported. Therefore, we studied the potential of this diterpenoid to inhibit liver cirrhosis induced by thioacetamide, a model that shares many similarities with the human disease, and investigated the possible underlying molecular mechanism using in vivo and in vitro approaches. Cirrhosis was induced in male Wistar rats by chronic thioacetamide administration (200 mg/kg) intraperitoneally three times per week. Rats received saline or SVT (20 mg/kg) two times daily intraperitoneally. In addition, co‐cultures were incubated with either lipopolysaccharide or ethanol. Liver fibrosis, hepatic stellate cells activation, metalloproteinases activity, canonical and non‐canonical Smads pathway and expression of several profibrogenic genes were evaluated. Thioacetamide activated hepatic stellate cells and distorted the liver parenchyma with the presence of abundant thick bands of collagen. In addition, thioacetamide up‐regulated the protein expression of α‐smooth muscle actin, transforming growth factor‐β1, metalloproteinases‐9,‐2 and ‐13 and overstimulate the canonical and non‐canonical Smad pathways. SVT administration inhibited all of these changes. In vitro, SVT inhibited the up‐regulation of several genes implicated in cirrhosis when cells were exposed to lipopolysaccharides or ethanol. We conclude that SVT inhibited liver damage by blocking hepatic stellate cells activation, down‐regulating canonical and non‐canonical profibrotic Smad pathways.     

PODOCYTE INJURY IS SUPPRESSED BY 1,25-DIHYDROXYVITAMIN D3 VIA MODULATION OF TRANSFORMING GROWTH FACTOR-β1/BONE MORPHOGENETIC PROTEIN-7 SIGNALLING IN PUROMYCIN AMINONUCLEOSIDE NEPHROPATHY RATS

• 1 Accumulating evidence suggests that vitamin D and its analogues are renoprotective. However, the precise mechanisms and the molecular targets by which active vitamin D exerts its beneficial effects remain obscure. The objective of the present study was to evaluate the effect of active vitamin D on rats with puromycin aminonucleoside (PAN) nephropathy, a model that is characterized by predominant podocyte injury.
• 2 The PAN nephropathy rats were created by a single intravenous injection of 100 mg/kg PAN. Changes in renal pathology and podocyte numbers were observed. Real‐time polymerase chain reaction (PCR) was performed to examine mRNA expression of nephrin, transforming growth factor (TGF)‐β1 and bone morphogenetic protein (BMP)‐7. Protein expression of nephrin, TGF‐β1, BMP‐7 and p‐Smad2/3 and p‐Smad1/5/8 was examined by immunofluorescence, immunohistochemistry and western blotting, respectively. Rats were treated with 1,25(OH)₂D₃ by gastric gavage at a dose of 2.5 µg/kg per day, starting 2 days before PAN injection and continuing throughout the experiment.
• 3 A single injection of PAN induced massive proteinuria and elevated serum creatinine on Day 7, both of which were significantly suppressed by 1,25‐dihydroxyvitamin D₃ (1,25(OH)₂D₃). Immunofluorescence and real‐time PCR of the podocyte‐associated protein nephrin revealed reduced and discontinuous staining and this change was reversed by 1,25(OH)₂D₃. In PAN nephropathy rats, TGF‐β1 and p‐Smad2/3 expression was upregulated, whereas that of BMP‐7 and p‐Smad1/5/8 was downregulated. Treatment with 1,25(OH)₂D₃ significantly restored BMP‐7/Smad signalling while suppressing TGF‐β1/Smad signalling.
• 4 In conclusion, 1,25(OH)₂D₃ can ameliorate podocyte damage and proteinuria induced by PAN. The beneficial effects of 1,25(OH)₂D₃ on podocytes may be attributable, in part, to direct modulation of TGF‐β1/BMP‐7 signalling.

     

Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL

The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl₄ injection. Furthermore, TGF-β1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and α-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-β1-activated human LX-2 cells and resulted in an increased expression of α-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of α-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis.     

Opposite actions of urotensin II and relaxin‐2 on cellular expression of fibronectin in renal fibrosis: A preliminary experimental study

Our aim was to evaluate the role of urotensin II, urantide (urotensin II receptor antagonist) and relaxin‐2 on the cellular expression of fibronectin as a surrogate marker for renal fibrosis. We employed LLC‐PK1 renal tubular epithelial cells and assessed the influence on the fibrotic process of the above‐mentioned substances by using anti‐fibronectin antibodies in western blot analysis. The addition of urotensin II increased fibronectin expression. Urantide reduced the positivity for fibronectin caused by urotensin II (P<.05). The anti‐fibrotic action was more evident for relaxin‐2 (P<.01). Also in the model of TGF‐β1‐induced fibrosis, urantide and, to a greater extent, relaxin‐2 were able to significantly lessen fibronectin expression (respectively, P<.05 and P<.01). In conclusion, relaxin‐2 may reduce urotensin II‐induced renal fibrosis.     

MiR‐101a ameliorates AngII‐mediated hypertensive nephropathy by blockade of TGFβ/Smad3 and NF‐κB signalling in a mouse model of hypertension

Hypertensive nephropathy, clinically characterized by progressive renal fibrosis and inflammation, is a severe complication of hypertension. The objectives of this study were to investigate the roles of miR‐101a in relieving angiotensin II (Ang II)‐mediated hypertensive nephropathy and uncover the possible underlying mechanisms. A hypertensive mouse model was established via continuous 28‐day AngII infusion. Systolic blood pressure (SBP), ratio of urine albumin to creatinine, blood urea nitrogen (BUN), serum creatinine (Scr) and glomerular filtration rate (GFR) were evaluated. Dual luciferase reporter assay was used to explore the target of miR‐101a. mRNA levels of miR‐101a, TGFβRI, fibrotic markers (Collagen I and α‐SMA) and pro‐inflammatory cytokines (IL‐1β and TNF‐α) were determined by real‐time PCR. Protein levels of TGFβRI, Collagen I, α‐SMA, IL‐1β, TNF‐α, t‐p65, P‐p65, t‐Smad3, P‐Smad3, t‐IκBα and P‐IκBα were detected by western blot. MiR‐101a mimics significantly improved GFR and inhibited AngII‐induced increase in the ratio of urine albumin to creatinine, BUN and Scr. MiR‐101a mimics partially abolished AngII‐induced increase in the mRNA and protein level of fibrotic markers by targeting TGFβRI and inhibiting TGFβ/Smad3 pathway. Moreover, TGFβRI inhibitor galunisertib inhibited AngII‐mediated renal injury in mice with hypertensive nephropathy. Additionally, miR‐101a overexpression blocked AngII‐induced up‐regulation of pro‐inflammatory markers via suppressing NF‐κB pathway. MiR‐101a exhibited protective effects against hypertensive nephropathy via inhibiting TGFβ/Smad3 and NF‐κB signalling pathways.