NUAK1 promotes organ fibrosis via YAP and TGF-ß/SMAD signaling.

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor-ß (TGF-ß)-driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-ß-inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-ß induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-ß/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.

Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis.

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.

A common glomerular transcriptomic signature distinguishes diabetic kidney disease from other kidney diseases in humans and mice.

BACKGROUND: Current uncertainties about the similarity between human diseases and their experimental models are hampering the development of new therapies. This is especially the case for diabetic kidney disease (DKD), the most common cause of end-stage kidney disease. To better understand the nature of the commonality between humans and their mouse models, we posed the question: in diabetic kidney disease are transcriptional profiles primarily disease-specific or species-specific? METHODS: We performed a meta-comparison of the glomerular transcriptomic characteristics of 133 human and 66 mouse samples including five human kidney diseases and five mouse models, validating expression patterns of a central node by immunohistochemistry. FINDINGS: Principal component analysis controlled for mouse background, revealed that gene expression changes in glomeruli from humans with DKD are more similar to those of diabetic mice than they are to other human glomerular diseases. This similarity enabled the construction of a discriminatory classifier that distinguishes diabetic glomeruli from other glomerular phenotypes regardless of their species of origin. To identify where the commonality between mice and humans with diabetes lies, networks of maximally perturbed protein interactions were examined, identifying a central role for the epidermal growth factor receptor (EGFR). By immunohistochemical staining, we found EGFR to be approximately doubled in its glomerular expression in both humans and mice. INTERPRETATION: These findings indicate that diabetic mouse models do mimic some of the features of human kidney disease, at least with respect to their glomerular transcriptomic signatures, and they identify EGFR as being a central player in this inter-species overlap.

A new, easily generated mouse model of diabetic kidney fibrosis.

Our understanding of diabetic kidney disease pathogenesis has been hampered by the lack of easily generated pre-clinical animal models that faithfully recapitulate critical features of human disease. While most standard animal models develop manifestations of early stage diabetic injury such as hyperfiltration and mesangial matrix expansion, only a select few develop key late stage features such as interstitial fibrosis and reduced glomerular filtration rate. An underlying theme in these late stage disease models has been the addition of renin-angiotensin system hyperactivation, an important contributor to human disease pathogenesis. Widespread use of these models has been limited, however, as they are either labour intensive to generate, or have been developed in the rat, preventing the use of the many powerful genetic tools developed for mice. Here we describe the Akita+/- Ren+/- mouse, a new, easily generated murine model of diabetic kidney disease that develops many features of late stage human injury, including not only hyperglycemia, hypertension, and albuminuria, but also reduced glomerular filtration rate, glomerulosclerosis, and interstitial fibrosis.

YAP/TAZ Are Mechanoregulators of TGF-ß-Smad Signaling and Renal Fibrogenesis.

Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-ß responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-ß In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-ß-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-ß stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-ß to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-ß/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-ß signaling and renal fibrogenesis.

Severe respiratory insufficiency during pandemic H1N1 infection: prognostic value and therapeutic potential of pulmonary surfactant protein A.

For almost two decades, studies have shown collectins to be critical for effective antimicrobial defense of the airways. Members of this protein family, which includes surfactant proteins (SP)-A and D, provide broad-spectrum protection through promoting the aggregation and clearance of pathogens. Interestingly, these proteins may also modulate the immune response, and growing evidence has shown collectins to be protective against several markers of inflammation and injury. In a recent study by Herrera-Ramos and colleagues, genetic variants of collectins were examined in Spanish patients with the pandemic 2009 H1N1 influenza A virus. Comparing genotypes for measures of poor lung function, inflammation, and admission to intensive care, these authors identified three variants of the SP-A gene SFTPA2 that positively correlated with flu severity. Remarkably, they also found the haplotype 1A(1) of SFTPA2 to be protective against these indicators, suggesting that targeted therapy with a recombinant form of SP-A2 may improve patient outcome. Although further work is required to confirm the specificity and efficacy of SP-A in therapeutic H1N1 protection, this study is one of the first to suggest a clinical role for SP-A in pandemic influenza.

Manejo del potasio por el riñón: trasplantado / Managing of the potassium for the kidney: transplanted

Se estudiaron 40 trasplantados renales con función renal estable y 30 individuos sanos como control. Se excluyeron los pacientes que presentaban creatinina sérica superior a 2 mg/dl, concentración de sodio en orina menor de 25 mEq/L y una fracción excretada de sodio menor de 0.4 por ciento. De esta manera fueron analizados 31 trasplantados renales y 25 controles. Los tasplantados recibían: ciclosporina, prednisona, azatioprina, micofenolato y bloqueantes cálcicos. Se aplicó la técnica de clearences de 2 horas. Se calculó gradiente transtubular de K mas (GTTK). Posteriormente, 16 trasplantados y 9 controles recibieron 2 dosis de 75 mg de diclofenato sódico y se repitieron las pruebas. Se utilizó el test de la T de Student para datos apareados y no apareados. ANOVA para cambios secuenciales en el tiempo. Como soporte informático Microsoft Word, Power Point y Stat View 4.5 de Abacus. Los resultados mostraron diferencias en el GTTK entre trasplantados y controles tras recibir el diclofenato sódico (5,6  3,6 vs 11,9  3,5 respectivamente, p mayor 0.0003). Esto indicaría una mayor excreción de K más por los controles. Al ajustar los resultados.por unidad de tiempo y volumen urinario, se detectó una disminución en la excreción renal de K más por los trasplantados, (0,018  0,012 vs 0,069  0,028 mEq/ml/min; p mayor 0.001). Esto hace suponer que se sobrestimó al GTTK producto de un flujo urinario reducido. En conclusión, la administración de diclofenato sódico induce en el riñón trasplantado alteraciones en la secreción de potasio a nivel de la nefrona distal. El mecanismo por el cual los riñones trasplantados presentan esta dificultad, podría obedecer al tratamiento con ciclosporina, que además inhibir la síntesis de prostaglandinas, bloquearía la Na más/K más/ATPasa basolateral, comprometiendo la secreción de K más, evidenciada al recibir diclofenato sódico.