Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic ...effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies.
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Highlights • The vascular phenotypes of Klotho deficiency and aged human vasculature are similar. • The protective effects of Klotho are conferred to the vasculature by soluble Klotho. • Experimental ...Klotho overexpression protects against many vascular diseases. • In vascular calcification, senescence is more important than hyperphosphataemia. • Membrane-bound Klotho protein is probably not expressed in the human vasculature.
Aims
Sodium–glucose co‐transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition ...with empagliflozin (EMPA) on cardiac function in non‐diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI).
Methods and results
Non‐diabetic male Sprague–Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA‐early) or 2 weeks after surgery (EMPA‐late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two‐fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA‐early and EMPA‐late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production.
Conclusion
Empagliflozin favourably affects cardiac function and remodelling in non‐diabetic rats with LV dysfunction after MI, associated with substantial improvements in cardiac metabolism and cardiac ATP production. Importantly, it did so without renal adverse effects. Our data suggest that EMPA might be of benefit in heart failure patients without diabetes.
Background and aims
Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of ...calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors.
Methods
We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all‐cause mortality. Causes of death were categorized according to ICD‐10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T50.
Results
The mean age was 64.2 ± 9.8 years, and 61% were male. The average serum T50 time was 323 ± 63 min. Higher age, alcohol use, high‐sensitive C‐reactive protein, and plasma phosphate were associated with lower serum T50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow‐up of 7.55.4–10.7 years, each 60 min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08–1.50, and p = 0.01) and all‐cause mortality (HR 1.15, 95%CI 1.00–1.38, and p = 0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60 mL/min/1.73 m2 and higher plasma phosphate levels.
Conclusions
Serum T50 improves prediction of cardiovascular and all‐cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D.
Summary
Acceptance criteria of deceased donor organs have gradually been extended toward suboptimal quality, posing an urgent need for more objective pre‐transplant organ assessment. Ex vivo ...normothermic machine perfusion (NMP) combined with magnetic resonance imaging (MRI) could assist clinicians in deciding whether a donor kidney is suitable for transplantation. Aim of this study was to characterize the regional distribution of perfusate flow during NMP, to better understand how ex vivo kidney assessment protocols should eventually be designed. Nine porcine and 4 human discarded kidneys underwent 3 h of NMP in an MRI‐compatible perfusion setup. Arterial spin labeling scans were performed every 15 min, resulting in perfusion‐weighted images that visualize intrarenal flow distribution. At the start of NMP, all kidneys were mainly centrally perfused and it took time for the outer cortex to reach its physiological dominant perfusion state. Calculated corticomedullary ratios based on the perfusion maps reached a physiological range comparable to in vivo observations, but only after 1 to 2 h after the start of NMP. Before that, the functionally important renal cortex appeared severely underperfused. Our findings suggest that early functional NMP quality assessment markers may not reflect actual physiology and should therefore be interpreted with caution.
This study is the first to visualize the regional distribution of renal perfusate flow with magnetic resonance techniques during the first hours of warm ex vivo perfusion in porcine and human kidneys.
Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy ...(DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk
via
intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.
Renal fibrosis leads to end‐stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN‐γ is an antifibrotic cytokine that may attenuate renal fibrosis. ...Systemically administered IFN‐γ causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell‐specific delivery of IFN‐γ to platelet‐derived growth factor receptor β (PDGFRβ)‐expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy unilateral ureteral obstruction (UUO) mouse model. PEGylated IFN‐γ conjugated to PDGFRβ‐recognizing peptide (PPB)‐polyethylene glycol (PEG)‐IFN‐γ was tested in vitro and in vivo for antifibrotic properties and compared with free IFN‐γ. PDGFRβ expression was >3‐fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with α‐smooth muscle actin‐positive (SMA+) myofibroblasts. In vitro, PPB‐PEG‐IFN‐γ significantly inhibited col1a1, col1a2, and α‐SMA mRNA expression in TGF‐β‐activated NIH3T3 fibroblasts (P < 0.05). In vivo, PPB‐PEG‐IFN‐γ specifically accumulated in PDGFRβ‐positive myofibroblasts. PPB‐PEG‐IFN‐γ treatment significantly reduced renal collagen I, fibronectin, and α‐SMA mRNA and protein expression. Compared with vehicle treatment, PPB‐PEG‐IFN‐γ preserved tubular morphology, reduced interstitial T‐cell infiltration, and attenuated lymphangiogenesis (all P < 0.05) without affecting peritubular capillary density. PPB‐PEGIFN‐γ reduced IFN‐γ‐related side effects as manifested by reduced major histocompatibility complex class II expression in brain tissue (P < 0.05 vs. free IFN‐γ). Our findings demonstrate that specific targeting of IFN‐γ to PDGFRβ‐expressing myofibroblasts attenuates renal fibrosis and reduces systemic adverse effects.—Poosti, F., Bansal, R., Yazdani, S., Prakash, J., Post, E., Klok, P., vanden Born J. deBorst M.H. vanGoor H. Poelstra K. Hillebrands, J.‐L. Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis. FASEB J. 29, 1029–1042 (2015). www.fasebj.org
Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial inhibitory effect of ...dapagliflozin, a SGLT2 inhibitor, on TIF, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing TIF as well as its possible impact on renal function. TIF in human kidney biopsies obtained from patients with DN was quantified by histopathological staining.
, HK-2 cells were incubated in high glucose with dapagliflozin or fludarabine, and epithelial-mesenchymal transition (EMT) was determined.
experiments were performed in streptozotocin (STZ)-induced type 1 diabetic mice treated with dapagliflozin by gavage for 16 weeks, after which specific functional characteristics and TIF were analyzed. In both DN patients and diabetic mice, fibronectin and Col IV, as well as STAT1 protein in the kidneys were increased as compared with controls. Dapagliflozin significantly decreased blood glucose, and renal STAT1 and TGF-β1 expression in mice. Furthermore, dapagliflozin improved renal function, and attenuated diabetes-induced TIF. In HK-2 cells, dapagliflozin, and fludarabine directly decreased aberrant STAT1 expression and reversed high glucose-induced downregulation of E-cadherin and α-SMA induction. Thus, the results demonstrate that dapagliflozin not only improves hyperglycemia but also slows down the progression of diabetes-associated renal TIF by improving hyperglycemia-induced activation of the STAT1/TGF-β1 pathway.
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