Experimental CKD Research Articles

Progenitor cell secretory products exert additive renoprotective effects when combined with ace inhibitors in experimental CKD.

Hypothesis/introduction:Renal fibrovascular injury often persists in chronic kidney disease patients treated with renin-angiotensin system blockers. Intriguingly, early outgrowth cell-derived factor infusion also inhibits chronic renal injury. We sought to determine whether early outgrowth cell-derived factor administration provides further renoprotection when added to renin-angiotensin system blockade.Materials and methods:Conditioned medium was generated by incubating rat early outgrowth cells with serum-free endothelial basal medium-2 to collect their secreted factors. Subtotal nephrectomy rats received enalapril 0.5 mg/L in drinking water or placebo, beginning 8 weeks post-surgery. Four weeks later, enalapril-treated rats received intravenous injections of either conditioned medium or control endothelial basal medium-2 for 2 weeks. Glomerular filtration rate, urinary protein excretion and renal structure were assessed 4 weeks later at 16 weeks post-surgery.Results:Enalapril-treated subtotal nephrectomy rats receiving control endothelial basal medium-2 injections experienced only partial renoprotection when compared to vehicle-treated subtotal nephrectomy rats. In contrast, conditioned medium infusion, when administered in addition to enalapril, attenuated the progression of renal dysfunction in subtotal nephrectomy rats, improving glomerular filtration rate and reducing proteinuria without affecting blood pressure.Conclusions:Early outgrowth cell-derived factors exert additive renoprotective effects on top of angiotensin-converting enzyme inhibitor therapy in experimental chronic kidney disease, providing the rationale for clinical trials of early outgrowth cell-based therapies for chronic kidney disease.

Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.

Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.

Death associated protein kinase 2 is expressed in cortical interstitial cells of the mouse kidney.

BackgroundDAPK2 is a pro-apoptotic protein kinase that associates with TGFβ receptors. The homolog DAPK1 has been shown to mediate apoptosis in kidney injury. Expression databases indicate that DAPK2 is expressed in the kidney, and in this work we investigate the localization of renal DAPK2 expression and its role in the kidney.ResultsImmunostaining demonstrates DAPK2 expression in interstitial cells of the renal cortex including PDGFRβ-positive pericytes and the CD73-positive erythropoietin-expressing fibroblast population. Tubulointerstitial fibrosis in experimental CKD arises directly from resident interstitial cells, and we therefore evaluated the expression of DAPK2 in the expanded interstitium of mice with kidney disease induced by chronic cisplatin administration. Expanded renal interstitium in these animals was negative for DAPK2 expression, but healthy areas of the kidney in which the tubular interstitium had not expanded expressed DAPK2 at levels similar to the uninjured control. Dapk2 null mice were generated to evaluate if DAPK2 is required for formation of the kidney, or its maintenance in the adult. Kidneys of Dapk2 null mice did not show overt malformations or age-related degeneration, but did show a slight increase in the number of interstitial fibroblasts. Differences were seen between Dapk2 null mice and wild type controls in the response to tubulointerstitial fibrosis caused by chronic cisplatin administration. Although mutant and wild type mice displayed comparable levels of alpha smooth muscle actin, interstitial proliferation and SMAD2 signaling, Dapk2 null mice showed reduced interstitial collagen accumulation.ConclusionsIn the kidney, DAPK2 is strongly and specifically expressed in interstitial cells of the cortex, providing a useful marker for this important cell population. Dapk2 null mice are phenotypically normal under steady state conditions, but display some resistance to extracellular matrix deposition in experimental renal fibrosis indicating that DAPK2 plays a profibrotic role in kidney injury.

Matrix Metalloproteinases and Their Inhibitors in Kidney Scarring: Culprits or Innocents

The renal extracellular matrix (ECM) is in a continual state of turnover with homeostasis maintained by balancing synthesis and degradation rates. During progressive kidney scarring an imbalance occurs leading to increase ECM either by increased deposition or decreased breakdown, although a combination of the two is more likely. Increased synthesis of many ECM proteins such as collagens I, III, and IV, fibronectin and laminin contribute to this imbalance; however decreased proteolytic activity leading to accumulation of ECM components is also an important component of scarring. The matrix metalloproteinases (MMPs) system is predominantly responsible for degrading mature ECM, consisting of 24 members, with MMP's 1, 2, 3, 8, 9, and 13 having significant renal expression. The kidney also expresses 3 Tissue inhibitors of MMPs; TIMP-1, 2, and 3. MMPs also have a role during kidney development. Several studies describe changes in ECM proteolysis and more specifically MMPs in end stage kidney disease (ESRD), although most of these are descriptive and based on enzymatic, protein or mRNA analysis of homogenates. There is no consistency in most of these studies regarding the expression of MMPs and TIMPS in experimental kidney scarring. Few of these studies have been investigated in human kidney scarring. Here is a comprehensive review of the MMPs and TIMPs literature including their action, activation, regulation, and contribution in experimental and human CKD.

223: Left Ventricular Dysfunction is Associated with Iron Deficiency in Rats with Experimental CKD

223: Left Ventricular Dysfunction is Associated with Iron Deficiency in Rats with Experimental CKD