Although yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), nuclear transducers of the Hippo pathway, are mostly silent in adult organs, aberrant activation of YAP/TAZ promotes tumorigenesis and abnormal tissue repair. The extent of involvement of TAZ in chronic kidney disease (CKD) is unknown. In our study, increased TAZ nuclear accumulation and expression in the tubulointerstitium was readily evident in 3 models of renal injury including obstructive, aristolochic acid (AA), and diabetic nephropathy, correlating with fibrosis progression. Stable TAZ overexpression in human kidney (HK)-2 epithelial cells promoted connective tissue growth factor (CTGF), fibronectin, vimentin, and p21 expression, epithelial dedifferentiation, and growth inhibition, in part, via Sma mothers against decapentaplegic homologue (SMAD)-3-dependent CTGF induction. CTGF secretion by TAZ-overexpressing epithelium also triggered proliferative defects in nonengineered HK-2 cells confirming a nonautonomous role of TAZ ( via a paracrine mechanism) in orchestrating kidney epithelial cell-cell communication. Renal tubular-specific induction of TGF-β1 in mice and TGF-β1 stimulation of HK-2 cells resulted in TAZ protein up-regulation. TAZ stable silencing in HK-2 cells abrogated TGF-β1-induced expression of target genes without affecting SMAD3 phosphorylation, which is also crucial for fibrotic reprogramming. Thus, TAZ was activated in fibrosis through TGF-β1-dependent mechanisms and sustained TAZ signaling promotes epithelial maladaptive repair. TAZ is also a novel non-SMAD downstream effector of renal TGF-β1 signaling, establishing TAZ as a new antifibrosis target for treatment of CKD.-Anorga, S., Overstreet, J. M., Falke, L. L., Tang, J., Goldschmeding, R. G., Higgins, P. J., Samarakoon, R. Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype.

The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

Rac‐GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF‐β1 promoted rapid Rac1‐GTP loading in human kidney 2 (HK‐2) human renal epithelial cells. A Rac‐specific chemical inhibitor, EHT 1864, blocked TGF‐β1‐induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK‐2 cells, moreover, eliminated TGF‐β1‐mediated non‐SMAD pathway activation [e.g., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor‐1 (PAI‐1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22phox knockdown abrogated free radical generation by TGF‐β1 in HK‐2 cells, consistent with the role of Rac1 in NAPD(H). TGF‐β1‐induced renal epithelial cytostasis was also completely bypassed by Rac1, p22phox, p47phox, and PAI‐1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction‐driven EGFR, p53, Rac1b, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle‐treated obstructed kidneys. Thus, the Rac1‐directed redox response is critical for TGF‐β1‐driven epithelial dysfunction orchestrated, in part, via PAI‐1 up‐regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.—Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 33, 9797–9810 (2019). http://www.fasebj.org

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The development of efficient visible‐light‐driven photocatalysts is one of the critically important issues for solar hydrogen production. Herein, high‐efficiency visible‐light‐driven In2O3/CdZnS hybrid photocatalysts are explored by a facile oil‐bath method, in which ultrafine CdZnS nanoparticles are anchored on NH2‐MIL‐68‐derived fusiform In2O3 mesoporous nanorods. It is disclosed that the as‐prepared In2O3/CdZnS hybrid photocatalysts exhibit enhanced visible‐light harvesting, improves charges transfer and separation as well as abundant active sites. Correspondingly, their visible‐light‐driven H2 production rate is significantly enhanced for more than 185 times to that of pristine In2O3 nanorods, and superior to most of In2O3‐based photocatalysts ever reported, representing their promising applications in advanced photocatalysts.

Hypoxia during pregnancy could affect development of fetuses as well as cardiovascular systems in the offspring. This study was the first to demonstrate the influence and related mechanisms of prenatal hypoxia (PH) on renal interlobar arteries (RIA) in the 5-month-old male rat offspring. Following chronic hypoxia during pregnancy, phenylephrine induced significantly higher pressor responses and greater vasoconstrictions in the offspring. Nitric oxide mediated vessel relaxation was altered in the RIA. Phenylephrine-stimulated free intracellular calcium was significantly higher in the RIA of the PH group. The activity and expression of L-type calcium channel (Cav1.2), not T-type calcium channel (Cav3.2), was up-regulated. The whole-cell currents of calcium channels and the currents of Cav1.2 were increased compared with the control. In addition, the whole-cell K+ currents were decreased in the offspring exposed to prenatal hypoxia. Activity of large-conductance Ca2+-activated K+ channels and the expression of MaxiKα was decreased in the PH group. The results provide new information regarding the influence of prenatal hypoxia on the development of the renal vascular system, and possible underlying cellular and ion channel mechanisms involved.

Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan–Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.

Rechargeable aqueous proton batteries are promising competitors for the next generation of energy storage systems with the fast diffusion kinetics and wide availability of protons. However, poor cycling stability is a big challenge for proton batteries due to the attachment of water molecules to the electrode surface in acid electrolytes. Here, a hydrogen‐bond disrupting electrolyte strategy to boost proton battery stability via simultaneously tuning the hydronium ion solvation sheath in the electrolyte and the electrode interface is reported. By mixing cryoprotectants such as glycerol with acids, hydrogen bonds involving water molecules are disrupted leading to a modified hydronium ion solvation sheaths and minimized water activity. Concomitantly, glycerol absorbs on the electrode surface and acts to protect the electrode surface from water. Fast and stable proton storage with high rate capability and long cycle life is thus achieved, even at temperatures as low as −50 °C. This electrolyte strategy may be universal and is likely to pave the way toward highly stable aqueous energy storage systems.