Losartan Improved Antioxidant Defense, Renal Function and Structure of Postischemic Hypertensive Kidney

Ischemic acute renal failure (ARF) is a highly complex disorder involving renal vasoconstriction, filtration failure, tubular obstruction, tubular backleak and generation of reactive oxygen species. Due to this complexity, the aim of our study was to explore effects of Angiotensin II type 1 receptor (AT1R) blockade on kidney structure and function, as well as oxidative stress in spontaneously hypertensive rats (SHR) after renal ischemia reperfusion injury. Experiments were performed on anaesthetized adult male SHR in the model of ARF with 40 minutes clamping the left renal artery. The right kidney was removed and 40 minutes renal ischemia was performed. Experimental groups received AT1R antagonist (Losartan) or vehicle (saline) in the femoral vein 5 minutes before, during and 175 minutes after the period of ischemia. Biochemical parameters were measured and kidney specimens were collected 24h after reperfusion. ARF significantly decreased creatinine and urea clearance, increased LDL and lipid peroxidation in plasma. Treatment with losartan induced a significant increase of creatinine and urea clearance, as well as HDL. Lipid peroxidation in plasma was decreased and catalase enzyme activity in erythrocytes was increased after losartan treatment. Losartan reduced cortico-medullary necrosis and tubular dilatation in the kidney. High expression of pro-apoptotic Bax protein in the injured kidney was downregulated after losartan treatment. Our results reveal that angiotensin II (via AT1R) mediates the most postischemic injuries in hypertensive kidney through oxidative stress enhancement. Therefore, blockade of AT1R may have beneficial effects in hypertensive patients who have developed ARF

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Apoptosis, mitosis, PCNA and bcl-2 in normal, leukoplakic and malignant epithelia of the human oral cavity: Prospective, in vivo study

Disordered balance between proliferation and apoptosis may contribute to carcinogenesis. Thirty-two oral biopsies were collected prospectively: 10 normal (N), 10 leukoplakia (dysplasia, D = 5; hyperplasia, H = 5) and 12 squamous cell carcinoma (C: 11). Distant normal tissue was also collected (HN, DN, CN). Based on counts of 1000 cells/slide, mitotic (MI), apoptotic(AI) and proliferating cell nuclear antigen (PCNA: PI) indices were calculated and bcl-2 expression recorded. AI correlated with MI (

Heavy metal imaging in fibrotic human kidney tissue using the synchrotron X-ray fluorescence microprobe

Abnormally high exposure to heavy metals and their accumulation in some tissues are recognized as causes of many acute and chronic human diseases. Because of the roles many metals have in normal human physiology, proving cause and effect between exposure to heavy metals and pathogenesis of disease is problematic. Therefore, many illnesses that develop through occupational and environmental exposure are not considered directly related to heavy metal toxicity. The high sensitivity and spatial resolution of elements using the synchrotron X-ray fluorescence microprobe (XFM) may give a robust means to investigate spatial distribution of heavy metals in correlation with specific pathologies. For example, proven presence of different heavy metals may correlate spatially with kidney fibrosis, suggesting a mechanistic link between heavy metal-induced fibrosis and chronic kidney disease. One specific example that may benefit from such an analysis relates to a cluster of people with chronic kidney disease of unknown cause (CKDu), in a significant proportion of the population of the North Central Province of Sri Lanka. Here, it was postulated that heavy metal exposure, in particular of cadmium, in foods and agriculture may be one cause of end-stage kidney disease and premature death of patients with CKDu. Synchrotron methods had not been applied previously to this particular problem. This manuscript provides a brief review of the literature and reports some pilot data from an investigation of localization of kidney fibrosis in CKDu with selected heavy metals including cadmium