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We have previously demonstrated that transforming growth factor-[[beta].sub.1] (TGF-[[beta].sub.1]) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257-47262, 2002). In the present study, we investigated the functional role of upstream TGF-[beta]-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-[[beta].sub.1] signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-[[beta].sub.1] was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-[[beta].sub.1] stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-[[beta].sub.1]-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38[alpha] MAPK activity by ectopic expression of either TAB1 or wild-type p38[alpha] MAPK resulted in enhanced TGF-[[beta].sub.1]-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-[[beta].sub.1]. In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. mouse mesangial cell; TGF-[beta] signaling; stable transfection; dominant negative mutant of TAK1 doi:10.1152/ajprenal.00485.2006

Transplant recipients are vulnerable to infections, including COVID‐19, given their comorbidities and chronic immunosuppression. In this study, all hospitalized renal transplant recipients (RTR) with a positive nasal swab for Severe Acute Respiratory Syndrome‐Coronavirus‐2 (SARS‐CoV2) seen consecutively between 03/01/2020 and 05/01/2020 at the Detroit Medical Center were included. Data on demographics, clinical presentation, laboratory findings, management, and outcomes were collected. Twenty‐five patients were included, all African American (AA) and deceased‐donor transplant recipients. The most common presenting symptom was dyspnea, followed by fever, cough and diarrhea. Multifocal opacities on initial chest x‐ray were seen in 52% patients and 44% of patients had a presenting oxygen saturation of less than or equal to 94%. Four patients (16%) required transfer to the intensive care unit, one required intubation and one expired. COVID‐19‐infected RTR in this cohort had low mortality of 4% (n = 1). Despite multiple comorbidities and chronic immunosuppression, our cohort of African American RTR had favorable outcomes compared to other reports on COVID‐19 in RTR. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction complicates hypertension and is a precursor of atherosclerosis. It is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in the activity of vasoconstrictors, including angiotensin (Ang) II and reactive oxygen species (ROS). To the extent that cardiovascular disease is characterized by an imbalance between NO, Ang II, and ROS in the endothelium, modulating the activity of these vasoactive substances has important implications for both the treatment of hypertension and the prevention of atherosclerosis and end organ damage. Accumulating experimental and clinical data suggest that a multitherapy antihypertensive regimen that includes inhibitors of the renin-angiotensin system and calcium channel antagonists may further reduce cardiovascular risk via greater improvements in endothelial function, in addition to the well-documented blood pressure lowering effects. Experimental studies in small and large coronary arteries and in aorta indicate that the calcium channel blocker, amlodipine, stimulates NO generation. These drug-specific actions beyond blood pressure lowering may exert cardio- and vasculoprotective effects by preventing the maladaptive changes that accompany hypertension, namely endothelial dysfunction, upregulation of proinflammatory molecules, vascular smooth muscle cell (VSMC) growth and migration, and increased extracellular matrix deposition, mechanisms that lead to atherosclerotic cardiovascular disease. These effects compliment those of other classes of antihypertensive agents and also 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which have also been demonstrated to ameliorate the damaging consequences of endothelial dysfunction and thus reduce the incidence of cardiovascular events.