ABSTRACT
BACKGROUND: Soluble Klotho functions as an endocrine factor that plays important roles in a variety of pathophysiological processes. Soluble Klotho contains 130 KDa and 65 KDa isoforms. However, their distinct individual functional heterogeneity remains uncertain. Herein, we investigated the regulatory role of two soluble Klothos on cardiac fibrogenic responses. METHODS AND RESULTS: The effect of soluble Klothos on myofibroblast differentiation, proliferation, and collagen synthesis/degradation were examined in cultured mouse cardiac myofibroblasts. The role of 130 KDa Klotho on fibrosis in hypertensive heart disease were examined in wild type (WT) and Klotho transgenic (Tg/+) mice receiving chronic angiotensin (Ang)II infusion. Our in vitro studies revealed that addition of 130 KDa soluble Klotho isoform increased collagen synthesis in a dose dependent manner. Furthermore, 130 KDa Klotho significantly stimulated myofibroblast differentiation, proliferation, and ERK phosphorylation, which were abolished by fibroblast growth factor (FGF) receptor antagonist (SU5402). In contrast, 65 KDa soluble Klotho treatment significantly suppressed myofibroblast proliferation and collagen synthesis. In vivo study further demonstrated that chronic AngII infusion lead to cardiac fibrosis in both WT and Tg/+ mice. However, cardiac collagen, TGF-ß1, TIMP-2, and α-smooth muscle actin (SMA) levels were markedly upregulated in Tg/+ mice compared to WT cohort. CONCLUSION: Taken together, these findings implicate that 130 KDa soluble Klotho plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway, whereas 65 KDa soluble Klotho exerts an anti-fibrotic effect in cardiac myofibroblasts. Thus, two distinct isoforms of soluble Klotho appear to play the counter-regulatory roles in cardiac fibrogenic responses.
Subject(s)
Cardiomyopathies/etiology , Glucuronidase/physiology , Hypertension/complications , Myofibroblasts/physiology , Animals , Cell Differentiation , Collagen Type I/biosynthesis , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibroblast Growth Factors/metabolism , Fibrosis , Klotho Proteins , Male , Mice, Inbred C57BL , Primary Cell Culture , Protein Isoforms/metabolismSubject(s)
Acidosis/etiology , Anastomosis, Surgical/methods , Azotemia/etiology , Cystectomy/methods , Ileum , Intestinal Fistula , Jejunum , Urinary Bladder Fistula , Female , Humans , Ileum/pathology , Ileum/surgery , Intestinal Fistula/blood , Intestinal Fistula/complications , Intestinal Fistula/diagnosis , Intestinal Fistula/physiopathology , Intestinal Fistula/surgery , Jejunum/pathology , Jejunum/surgery , Middle Aged , Tomography, X-Ray Computed/methods , Treatment Outcome , Urinary Bladder Fistula/blood , Urinary Bladder Fistula/complications , Urinary Bladder Fistula/diagnosis , Urinary Bladder Fistula/physiopathology , Urinary Bladder Fistula/surgeryABSTRACT
OBJECTIVES: The study objective was to assess the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use and mortality in patients with chronic kidney disease (CKD). BACKGROUND: There is insufficient evidence about the association of ACEI or ARBs with mortality in patients with CKD. METHODS: A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 U.S. veterans with nondialysis CKD who were previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores using the Kaplan-Meier method and Cox models in "intention-to-treat" analyses and in generalized linear models with binary outcomes and inverse probability of treatment weights in "as-treated" analyses. RESULTS: The age of the patients at baseline was 75 ± 10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with a significantly lower risk of mortality both in the intention-to-treat analysis (hazard ratio: 0.81, 95% confidence interval: 0.78 to 0.84; p < 0.001) and the as-treated analysis with inverse probability of treatment weights (odds ratio: 0.37, 95% confidence interval: 0.34 to 0.41; p < 0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. CONCLUSIONS: In this large contemporary cohort of nondialysis-dependent patients with CKD, ACEI/ARB administration was associated with greater survival.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/mortality , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Receptors, Angiotensin/metabolism , Renal Insufficiency, Chronic/metabolismABSTRACT
We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO(ob) osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (α-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in α-SMA(+) MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells.
