Transforming growth factor-β (TGF-β) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-β and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-β has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-β signaling. Equally, TGF-β signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-β capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-β in promoting not only renal fibrosis but also protective responses of TGF-β signaling. We review, in particular, growing evidence that supports protective effects of TGF-β by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-β actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00365.2015

TGF-β signaling in the kidney: profibrotic and protective effects

The term “aristolochic acid nephropathy” (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies (formerly known as “Chinese herbs nephropathy”), or by the environmental contaminants in food (Balkan endemic nephropathy). It is frequently associated with urothelial malignancies. Although products containing AA have been banned in most of countries, AAN cases remain regularly reported all over the world. Moreover, AAN incidence is probably highly underestimated given the presence of AA in traditional herbal remedies worldwide and the weak awareness of the disease. During these two past decades, animal models for AAN have been developed to investigate underlying molecular and cellular mechanisms involved in AAN pathogenesis. Indeed, a more-in-depth understanding of these processes is essential to develop therapeutic strategies aimed to reduce the global and underestimated burden of this disease. In this regard, our purpose was to build a broad overview of what is currently known about AAN. To achieve this goal, we aimed to summarize the latest data available about underlying pathophysiological mechanisms leading to AAN development with a particular emphasis on the imbalance between vasoactive factors as well as a focus on the vascular events often not considered in AAN.

/pdf/an-integrated-view-of-aristolochic-acid-nephropathy-update-3yqee2glxe.pdf

An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature

Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3-dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.

/pdf/diverse-role-of-tgf-b-in-kidney-disease-44qsq7m4zu.pdf

Diverse Role of TGF-β in Kidney Disease.

Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed.

https://www.mdpi.com/1422-0067/22/15/7881/pdf

TGF-Beta as a Master Regulator of Diabetic Nephropathy.

Transforming growth factor-β (TGF-β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF-β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF-β-mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF-β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF-β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non-coding RNAs at transcriptional levels. More importantly, disease-specific Smad3-dependent long non-coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of TGF-β-driven renal fibrosis via non-coding RNAs and their translational capacities will be discussed in detail.

Transforming growth factor-β signalling in renal fibrosis: from Smads to non-coding RNAs.

// Xiao-Yu Dai 1,2,* , Li Zhou 1,2,* , Xiao-Ru Huang 1 , Ping Fu 2 and Hui-Yao Lan 1 1 Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China 2 Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China * These authors have contributed equally to this work Correspondence to: Hui Y Lan, email: // Ping Fu, email: // Keywords : chronic aristolochic acid nephropathy, Smad7, renal fibrosis, renal inflammation Received : January 26, 2015 Accepted : March 05, 2015 Published : March 30, 2015 Abstract Chronic Aristolochic Acid Nephropathy (AAN) is a progressive chronic kidney disease related to herb medicine However, treatment for chronic AAN remains ineffective We report here that Smad7 is protective and has therapeutic potential for chronic AAN In a mouse model of chronic AAN, progressive renal injury was associated with a loss of renal Smad7 and disruption of Smad7 largely aggravated the severity of chronic AAN as demonstrated by a significant increase in levels of 24-hour urinary protein excretion, serum creatinine, and progressive renal ﬁbrosis and inflammation In contrast, restored Smad7 locally in the kidneys of Smad7 knockout mice prevented the progression of chronic AAN Further studies revealed that worsen chronic AAN in Smad7 knockout mice was associated with enhanced activation of TGF-β/Smad3 and NF-κB signaling pathways, which was reversed when renal Smad7 was restored Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN

/pdf/smad7-protects-against-chronic-aristolochic-acid-nephropathy-1kzdmeyuh2.pdf

Smad7 protects against chronic aristolochic acid nephropathy in mice.

OBJECTIVE To explore the effect and mechanism of matrine on regulating renal tubulointerstitium expression of MMP-3, TIMP-1 and FN. METHODS Seventy male SD rats were randomly allocated to five groups: normal group, shame UUO group, UUO group, UUO group treated with fusinopril (F group), UUO group treated with large dose of matrine (E group) and UUO group treated with small dose of matrine (D group). The expression levels of MMP-3, TIMP-1 and FN of the rats were determined with immunohistochemistry at 7, 14 days of the experiment. RESULTS The expression levels of MMP-3 of the rats in the UUO group and treatment groups decreased significantly compared with the normal group and shame UUO group (P 0.05). The expression level of MMP-3 was negatively correlated with those of TIMP-1 and FN in the UUO group (P < 0.01). CONCLUSION Matrine decreases the expression of TIMP-1 and FN in the tubulointerstitium and increases the expression of MMP-3, which would delay the progression of renal tubulointerstitial fibrosis.

[Effect of matrine on regulating renal tubulointerstitial expression of MMP-3, TIMP-1 and FN].

OBJECTIVE To observe the effects of piperazine ferulate (PF) on synthesis of extracellular matrix and expression of connective tissue growth factor (CTGF) in transforming growth factor-betal (TGF-beta1) induced rat glomerular mesangial cells (GMC), and to investigate its mechanism on the prevention of glomerulosclerosis METHODS Rat HBZY-1 GMCs were cultured in vitro and divided into 5 groups: Normal control group, TGF-beta1-stimulated group, TGF-beta1 plus 50, 100, 200 ng/mL PF group The level of CTGF protein expression induced by TGF-beta1 was measured by immunocytochemistry, The mRNA expression of CTGF was evaluated by quantitative real time fluroscent polymerase chain reaction The expressions of fibronectin and collagen I were analyzed by enzyme linked immunosorbent assay (ELISA) RESULTS With the stimulation of TGF-beta1, the expression of of CTGF protein and mRNA, as well as fibronectin and collagen I were markly increased (P < 005), which then were decreased by the treatment of PF (P < 005) CONCLUSION PF can partly inhibit synthesis of the extracellular matrix and CTGF PF may take part in the prevention of glomerulosclerosis through the inhibition of CTGF expression

[Effects of piperazine ferulate on connective tissue growth factor and extracellular matrix in TGF-beta1 induced mesangial cells].

Objective To determine the association of diabetes and glycemic control with early failure of native arteriovenous fistula(AVF). Methods 266 patients with end stage renal diseases(ESRD) were recruited and divided into non-diabetic group (165), HbA1C or = 7% group (50). Clinical indicators and early failure of AVF were examined. Results In total, 63 (23.7%) patients had AVF early failure. The AVF early failure occurred in 18. 1% of patients in the non-diabetic group and 21.6% of patients in the HbA1C or = 7% group (44%). The COX regression model showed that increased HbA1C, total cholesterol (TC) and decreased high-density lipoprotein (HDL)increased the risk of AVF failure. Conclusion The levels of glycemic and serum lipid subfractions are associated with AVF early failure in ESRD patients. Good control of glycemic and lipid can lower the rates of AVF early failure.

Association of diabetes and early failure of arteriovenous fistula in the end stage of renal diseases

A special intelligent liquid distribution machine for a dialysis machine comprises a mixing tank, a circulating pump, a pipeline connecting the mixing tank and the circulating pump, a magnetic valve V1, a magnetic valve V2, a magnetic valve V3 and a magnetic valve V4. The magnetic valve V1 is arranged between the mixing tank and a water inlet, the magnetic valve V2 and the magnetic valve V3 are connected in parallel between the mixing tank and the circulating pump, and the magnetic valve V4 is arranged between the circulating pump and a water outlet. Furthermore, the interior of the mixing tank is provided with a heater and a temperature sensor, a flowmeter is arranged between the water inlet and the magnetic valve V1, and a filter is arranged between the mixing tank and the magnetic valve V3. According to the special intelligent liquid distribution machine for the dialysis machine, the working process is free of manual intervention, liquid distribution, cleaning and disinfecting are integrated, the liquid distribution volume can be intelligently calculated, and quantitative concentrated solution can be distributed automatically; a plurality of sensors are set in the distributing process to conduct monitoring, prepared concentration is accurate, and thus liquid distribution intensity is greatly lowered.

Special intelligent liquid distribution machine for dialysis machine

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