Papers by Mahboob Chowdhury
Genetic diversity was investigated in 348 accessions and subaccessions of grasspea (Lathyrus sati... more Genetic diversity was investigated in 348 accessions and subaccessions of grasspea (Lathyrus sativus L.) from 10 geographical regions. Polymorphism for 20 isozymes of 13 enzyme systems was studied to estimate the genetic diversity. The Near East and North Africa regions included the most variability for these isozyme systems, suggesting that the center of diversity (center of origin) for grasspea is in this general area. The lowest variability was found in accessions and subaccessions from South America, followed by those from Sudan-Ethiopia. Diversity was measured for individual loci over regions and EST-1 and SKDH had the highest genetic diversity. The closest genetic diversity was observed for LAP-2, followed by AAT-1 and PGM. The closest genetic distance existed between populations from the Near East and North Africa. Populations from South Asia and Sudan-Ethiopia, though geographically widely separated, exhibited a closer genetic distance from each other than from other regions.
Nephrology Dialysis Transplantation, 2012
The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility... more The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability. Am J Physiol Renal Physiol 2009; 297: F85-F94. 19. Fan SC, Yu BC, Chen ZC et al. The decreased expression of peroxisome proliferator-activated receptors delta is reversed by digoxin in the heart of diabetic rats. Horm Metab Res 2010; 42: 637-642. 20. Matsushita Y, Ogawa D, Wada J et al. Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice.
Journal of the American Society of Nephrology : JASN, Jan 8, 2015
Evidence from multiple studies supports the concept that both glomerular filtration and proximal ... more Evidence from multiple studies supports the concept that both glomerular filtration and proximal tubule (PT) reclamation affect urinary albumin excretion rate. To better understand these roles of glomerular filtration and PT uptake, we investigated these processes in two distinct animal models. In a rat model of acute exogenous albumin overload, we quantified glomerular sieving coefficients (GSC) and PT uptake of Texas Red-labeled rat serum albumin using two-photon intravital microscopy. No change in GSC was observed, but a significant decrease in PT albumin uptake was quantified. In a second model, loss of endogenous albumin was induced in rats by podocyte-specific transgenic expression of diphtheria toxin receptor. In these albumin-deficient rats, exposure to diphtheria toxin induced an increase in albumin GSC and albumin filtration, resulting in increased exposure of the PTs to endogenous albumin. In this case, PT albumin reabsorption was markedly increased. Analysis of known alb...
Journal of the American Society of Nephrology : JASN, Jan 2, 2015
Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasin... more Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) µm(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) µm(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (...
Comparative medicine, 2013
Group B Streptococcus (Streptococcus agalactiae, GBS) is a gram-positive commensal and occasional... more Group B Streptococcus (Streptococcus agalactiae, GBS) is a gram-positive commensal and occasional opportunistic pathogen of the human vaginal, respiratory, and intestinal tracts that can cause sepsis, pneumonia, or meningitis in human neonates, infants, and immunosuppressed persons. We report here on a spontaneous outbreak of postnatal GBS-associated disease in rats. Ten of 26 (38.5%) 21- to 24-d-old rat pups died or were euthanized due to a moribund state in a colony of rats transgenic for the human diphtheria toxin receptor on a Munich-Wistar-Frömter genetic background. Four pups had intralesional coccoid bacteria in various organs without accompanying inflammation. GBS was isolated from the liver of 2 of these pups and from skin abscesses in 3 littermates. A connection with the transgene could not be established. A treatment protocol was evaluated in the remaining breeding female rats. GBS is a potentially clinically significant spontaneous infection in various populations of res...
Journal of the American College of Cardiology, 2015
Journal of the American College of Cardiology, 2015
Journal of the American Society of Nephrology : JASN, Jan 11, 2014
The attrition rate of functioning allografts beyond the first year has not improved despite impro... more The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed t...
Background: Peptidase inhibitor 3 (PI3) inhibits neutrophil elastase and proteinase-3, and has a ... more Background: Peptidase inhibitor 3 (PI3) inhibits neutrophil elastase and proteinase-3, and has a potential role in skin and lung diseases as well as in cancer. Genome-wide expression profiling of chorioamniotic membranes revealed decreased expression of PI3 in women with preterm premature rupture of membranes. To elucidate the molecular mechanisms contributing to the decreased expression in amniotic membranes, the PI3 gene was searched for sequence variations and the functional significance of the identified promoter variants was studied.
Kidney International, 2012
Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by... more Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to end stage kidney disease (ESKD). In order to determine mechanisms contributing to persistent podocyte loss, we used a human diphtheria toxin transgenic rat model. After initial diphtheria toxin-induced podocyte injury (over 30% loss in 4 weeks), glomeruli became destabilized, resulting in continued autonomous podocyte loss causing global podocyte depletion (ESKD) by 13 weeks. This was monitored by urine mRNA analysis and by quantitating podocytes in glomeruli. Similar patterns of podocyte depletion were found in the puromycin aminonucleoside and 5/6 nephrectomy rat models of progressive end-stage disease. Angiotensin II blockade (combined enalapril and losartan) restabilized the glomeruli, and prevented continuous podocyte loss and progression to ESKD. Discontinuing angiotensin II blockade resulted in recurrent glomerular destabilization, podocyte loss, and progression to ESKD. Reduction in blood pressure alone did not reduce proteinuria or prevent podocyte loss from destabilized glomeruli. The protective effect of angiotensin II blockade was entirely accounted for by reduced podocyte loss. Thus, an initiating event resulting in a critical degree of podocyte depletion can destabilize glomeruli and initiate a superimposed angiotensin II-dependent podocyte loss process that accelerates progression resulting in eventual global podocyte depletion and ESKD. These events can be monitored noninvasively in real-time through urine mRNA assays.
Journal of the American Society of Nephrology, 2013
The reduction in podocyte density to levels below a threshold value drives glomerulosclerosis and... more The reduction in podocyte density to levels below a threshold value drives glomerulosclerosis and progression to ESRD. However, technical demands prohibit high-throughput application of conventional morphometry for estimating podocyte density. We evaluated a method for estimating podocyte density using single paraffin-embedded formalin-fixed sections. Podocyte nuclei were imaged using indirect immunofluorescence detection of antibodies against Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; tumor-1 or transducin-like enhancer of split 4. To account for the large size of podocyte nuclei in relation to section thickness, we derived a correction factor given by the equation CF=1/(D/T+1), where T is the tissue section thickness and D is the mean caliper diameter of podocyte nuclei. Normal values for D were directly measured in thick tissue sections and in 3- to 5-μm sections using calibrated imaging software. D values were larger for human podocyte nuclei than for rat or mouse nuclei (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). In addition, D did not vary significantly between human kidney biopsies at the time of transplantation, 3-6 months after transplantation, or with podocyte depletion associated with transplant glomerulopathy. In rat models, D values also did not vary with podocyte depletion, but increased approximately 10% with old age and in postnephrectomy kidney hypertrophy. A spreadsheet with embedded formulas was created to facilitate individualized podocyte density estimation upon input of measured values. The correction factor method was validated by comparison with other methods, and provided data comparable with prior data for normal human kidney transplant donors. This method for estimating podocyte density is applicable to high-throughput laboratory and clinical use.
Journal of the American Society of Nephrology, 2013
Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (t... more Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P,0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P,0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimalchange disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.
Journal of the American Society of Nephrology, 2012
Podocyte depletion leads to glomerulosclerosis, but whether an impaired capacity of podocytes to ... more Podocyte depletion leads to glomerulosclerosis, but whether an impaired capacity of podocytes to respond to hypertrophic stress also causes glomerulosclerosis is unknown. We generated transgenic Fischer 344 rats that express a dominant negative AA-4E-BP1 transgene driven by the podocin promoter; a member of the mammalian target of rapamycin complex 1 (mTORC1) pathway, 4E-BP1 modulates cap-dependent translation, which is a key determinant of a cell's hypertrophic response to nutrients and growth factors. AA-4E-BP1 rat podocytes expressed the transgene and had normal kidney histology and protein excretion at 100 g of body weight but developed ESRD by 12 months. Proteinuria and glomerulosclerosis were linearly related to both increasing body weight and transgene dose. Uni-nephrectomy reduced the body weight at which proteinuria first developed by 40%-50%. The initial histologic manifestation of disease was the appearance of bare areas of glomerular basement membrane from the pulling apart of podocyte foot processes, followed by adhesions to the Bowman capsule. Morphometric analysis confirmed the mismatch between glomerular tuft volume and total podocyte volume (number 3 size) per tuft in relation to weight gain and nephrectomy. Proteinuria and glomerulosclerosis did not develop if dietary calorie restriction prevented weight gain and glomerular enlargement. In summary, failure of podocytes to match glomerular tuft growth in response to growth signaling through the mTORC1 pathway can trigger proteinuria, glomerulosclerosis, and progression to ESRD. Reducing body weight and glomerular growth may be useful adjunctive therapies to slow or prevent progression to ESRD.
Euphytica, 2001
... Mahboob A. Chowdhury1, Chandra P. Andrahennadi2, Alfred E. Slinkard3 & Albert Vandenberg3... more ... Mahboob A. Chowdhury1, Chandra P. Andrahennadi2, Alfred E. Slinkard3 & Albert Vandenberg3 1Greenhouse and Processing Crops Research Centre, Agriculture and Agri-Food Canada, 2585 Highway 20, E., Harrow, Ontario, Canada, NOR 1G0; 2Saskatchewan Wheat Pool ...
American Journal of Obstetrics and Gynecology, 2004
OBJECTIVE: Strong interest exists in offering first trimester Down syndrome screening based on co... more OBJECTIVE: Strong interest exists in offering first trimester Down syndrome screening based on combined nuchal translucency (NT) measurement and biochemistry. Our objective was to evaluate an alternate pathway for use in those populations in which skilled NT measurement is not readily available. Biochemical screening would be performed initially with NT measured contingent on serum results: Contingency Screening.
Nephrology Dialysis Transplantation, 2012
CH, Khoury CC et al. The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increa... more CH, Khoury CC et al. The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability. Am J Physiol Renal Physiol 2009; 297: F85-F94. 19. Fan SC, Yu BC, Chen ZC et al. The decreased expression of peroxisome proliferator-activated receptors delta is reversed by digoxin in the heart of diabetic rats. Horm Metab Res 2010; 42: 637-642. 20. Matsushita Y, Ogawa D, Wada J et al. Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. Diabetes 2011; 60: 960-968. 21. Cohen MP, Chen S, Ziyadeh FN et al. Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression, proteinuria, and diabetic nephropathy. Kidney Int 2005; 68: 1554-1561. 22. Lin CL, Wang FS, Hsu YC et al. Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes 2010; 59: 1915-1925. 23. Benigni A, Zoja C, Tomasoni S et al. Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-γ agonist: molecular mechanism of the antiproteinuric affect of pioglitazone. J Am Soc Nephrol 2006; 17: 1624-1632. 24. Ren S, Xin C, Beck KF et al. PPARα activation upregulates nephrin expression in human embryonic kidney epithelial cells and podocytes by a dual mechanism. Biochem Biophys Res Commun 2005; 338: 1818-1824. 25. Takata Y, Liu J, Yin F et al. PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis.
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Papers by Mahboob Chowdhury