Transforming growth factor-β (TGF-β) superfamily members are multifunctional growth factors that play pivotal roles in development and tissue homeostasis. Recent studies have underscored the importance of TGF-β in regulation of cell proliferation and extracellular matrix synthesis and deposition. TGF-β signaling is initiated by ligand binding to a membrane-associated receptor complex that has serine/threonine kinase activity. This receptor complex phosphorylates specific Smad proteins, which then transduce the ligand-activated signal to the nucleus. Smad complexes regulate target gene transcription either by directly binding DNA sequences, or by complexing with other transcription factors or co-activators. There is extensive crosstalk between the TGF-β signaling pathway and other signaling systems, including the mitogen-activated protein kinase pathways. The importance of TGF-β in regulation of cell growth has been emphasized by recent observations that mutations of critical elements of the TGF-β signaling system are associated with tumor progression in patients with many different types of epithelial neoplasms. TGF-β has emerged as a predominant mediator of extracellular matrix production and deposition in progressive renal disease and in other forms of chronic tissue injury. In this overview, recent advances in our understanding of TGF-β signaling, cell cycle regulation by TGF-β, and the role of TGF-β in progressive renal injury are highlighted.

Chronic allograft nephropathy (CAN) is characterized by progressive renal functional loss and histologic abnormalities of one or more tissue compartments. In this study, correlations between histologic abnormalities and graft function [glomerular filtration rate (GFR, measured by iothalamate clearance), serum creatinine (SCr) and urinary protein (UPr)] were investigated using biopsies from 49 patients with newly diagnosed CAN. Extent of tubulointerstitial fibrosis (%TIF), as assessed by a semi-quantitative score, correlated significantly with GFR, SCr and UPr. The close correlation between %TIF and GFR suggested that quantitative measurement of %TIF may predict functional consequences of CAN. Calculation of %TIF by computerized digital analysis was performed using four strategies: (a) quantitation of blue material in Masson's trichrome (MT)-stained sections, (b) quantitation of red material in Sirius Red-stained sections (SR-nonpolarized), (c) quantitation of birefringent material in Sirius Red stained-sections examined under polarized light (SR-polarized) and (d) quantification of brown material in sections stained by immunoperoxidase for alpha-smooth muscle actin. Only the SR-nonpolarized score correlated significantly with GFR at the time of biopsy-diagnosis of CAN. We conclude that digital analysis strategies demonstrate variable accuracy in quantifying %TIF. Validation of the SR-nonpolarized strategy against histologic scoring and GFR supports the application of this technique to longitudinal studies of CAN.

Introduction: Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened mammary tumor (MT) latency in MMTV-TGF-α mice with dietary-induced obesity. One link between obesity and breast cancer is the adipokine, leptin. Here, the focus is on diet-induced obesity and MT and mammary fat pad (MFP) leptin and apoptotic signaling proteins. Methods: MMTV-TGF-α mice were fed low-fat or high-fat diets from 10 to 85 weeks of age. High-Fat mice were divided into Obesity-Prone and Obesity-Resistant groups based on final body weights. Mice were followed to assess MT development and obtain serum, MFP, and MT. Results: Incidence of palpable MTs was significantly different: Obesity-Prone > Obesity-Resistant > Low-Fat. Serum leptin was significantly higher in Obesity-Prone compared with Obesity-Resistant and Low-Fat mice. Low-Fat mice had higher MFP and MT ObRb (leptin receptor) protein and Jak2 (Janus kinase 2) protein and mRNA levels in comparison with High-Fat mice regardless of body weight. Leptin (mRNA) and pSTAT3 (phosphorylated signal transducer and activator of transcription 3) (mRNA and protein) also were higher in MTs from Low-Fat versus High-Fat mice. Expression of MT and MFP pro-apoptotic proteins was higher in Low-Fat versus High-Fat mice. Conclusion: These results confirm a connection between body weight and MT development and between body weight and serum leptin levels. However, diet impacts MT and MFP leptin and apoptosis signaling proteins independently of body weight.

Unilateral renal artery stenosis (RAS) leads to atrophy of the stenotic kidney and compensatory enlargement of the contralateral kidney. Although the two-kidney, one-clip (2K1C) model has been extensively used to model human RAS, the cellular responses in the stenotic and contralateral kidneys, particularly in the murine model, have received relatively little attention. We studied mice 2, 5, and 11 wk after unilateral RAS. These mice became hypertensive within 1 wk. The contralateral kidney increased in size within 2 wk after surgery. This enlargement was associated with a transient increase in expression of phospho-extracellular signal-regulated kinase (p-ERK), the proliferation markers proliferating cell nuclear antigen and Ki-67, the cell cycle inhibitors p21 and p27, and transforming growth factor-β, with return to baseline levels by 11 wk. The size of the stenotic kidney was unchanged at 2 wk but progressively decreased between 5 and 11 wk. Unlike the contralateral kidney, which showed minimal histopathological alterations, the stenotic kidney developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Surprisingly, the stenotic kidney showed a proliferative response, which involved largely tubular epithelial cells. The atrophic kidney had little evidence of apoptosis, despite persistent upregulation of p53; expression of cell cycle regulatory proteins in the stenotic kidney was persistently increased through 11 wk. These studies indicate that in the 2K1C model, the stenotic kidney and contralateral, enlarged kidney exhibit a distinct temporal expression of proteins involved in cell growth, cell survival, apoptosis, inflammation, and fibrosis. Notably, an unexpected proliferative response occurs in the stenotic kidney that undergoes atrophy.

Rapid changes in the healthcare environment and public dissatisfaction with the cost and quality of medical care have prompted a critical analysis of how physicians are trained in the United States. Accrediting agencies have catalyzed a transformation from a process based to a competency-based curriculum, both at the undergraduate and the graduate levels. The objective of this overview is to determine how these changes are likely to alter the role of basic science in medical education. Policy statements related to basic science education from the National Board of Medical Examiners (NBME), the Accreditation Council for Graduate Medical Education (ACGME), American Board of Medical Specialties (ABMS), and the Federation of State Medical Boards (FSMB) were reviewed and assessed for common themes. Three primary roles for the basic sciences in medical education are proposed: (1) basic science to support the development of clinical reasoning skills; (2) basic science to support a critical analysis of medical and surgical interventions ("evidence-based medicine"); and (3) basic and translational science to support analysis of processes to improve healthcare ("science of healthcare delivery"). With these roles in mind, several methods to incorporate basic sciences into the curriculum are suggested.