Indra Gupta - Academia.edu (original) (raw)

Papers by Indra Gupta

International Journal of Molecular Sciences, Oct 2, 2019

Organogenesis, Jul 1, 2010

Journal of Cell Science, 2000

Bone morphogenetic protein (BMP)-2 and hepatocyte growth factor (HGF) exert antagonistic effects ... more Bone morphogenetic protein (BMP)-2 and hepatocyte growth factor (HGF) exert antagonistic effects on renal collecting duct formation during embryogenesis. A current model proposes HGF inhibits BMP-2 signaling at the level of Smad1 in a common target cell. Here, we show that BMP-2 and HGF control collecting duct formation via parallel pathways. We examined the interactions between BMP-2 and HGF in the mIMCD-3 model of collecting duct morphogenesis. During tubule formation, HGF rescued the inhibitory effects of BMP-2 and of a constitutive active form of the BMP-2 receptor, ALK3, stably expressed in mIMCD-3 cells. To determine whether the effect of HGF occurs through known mediators which act downstream of the BMP-2/ALK3 complex, we examined the effect of HGF on BMP-2-induced Smad1 phosphorylation, Smad1/Smad4 complex formation, and Smad1 nuclear translocation. Neither HGF nor other receptor tyrosine kinase ligands (EGF, FGF-4) induced phosphorylation of endogenous Smad1 in mIMCD-3 cell...

Journal of the American Society of Nephrology, 2013

Canadian Urological Association Journal, 2019

Introduction: To consider alternative mechanisms that give rise to a refluxing uretero-vesical ju... more Introduction: To consider alternative mechanisms that give rise to a refluxing uretero-vesical junction (UVJ), we hypothesized that children with a common heritable urinary tract defect, vesico-ureteric reflux (VUR), may have a defect in the extracellular matrix composition of the UVJ and other tissues that would be revealed by assessment of the peripheral joints. Hypermobile joints can arise from defects in the extracellular matrix within the joint capsule that affect proteins, including Tenascin XB. Methods: We performed an observational study of children with familial and non-familial VUR to determine the prevalence of joint hypermobility, renal scarring, and DNA sequence variants in Tenascin XB. Results: The majority of children, 27/44, exhibited joint hypermobility using the Beighton scoring system. This included 15/26 girls (57.6%) and 12/18 boys (66.6%), which is a significantly higher prevalence for both sexes when compared to population controls (p<0.005). We found no as...

The FASEB Journal, 2015

Claudins regulate the passage of ions and solutes between neighboring cells through tight junctio... more Claudins regulate the passage of ions and solutes between neighboring cells through tight junctions. The nephron is the functional unit of the kidney that filters the blood and removes excess water...

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International Journal of Molecular Sciences, 2021

The extracellular matrix of the bladder consists mostly of type I and III collagen, which are req... more The extracellular matrix of the bladder consists mostly of type I and III collagen, which are required during loading. During bladder injury, there is an accumulation of collagen that impairs bladder function. Little is known about the genes that regulate production of collagens in the bladder. We demonstrate that the transcription factor Odd-skipped related 1 (Osr1) is expressed in the bladder mesenchyme and epithelium at the onset of development. As development proceeds, Osr1 is mainly expressed in mesenchymal progenitors and their derivatives. We hypothesized that Osr1 regulates mesenchymal cell differentiation and production of collagens in the bladder. To test this hypothesis, we examined newborn and adult mice heterozygous for Osr1, Osr1+/−. The bladders of newborn Osr1+/− mice had a decrease in collagen I by western blot analysis and a global decrease in collagens using Sirius red staining. There was also a decrease in the cellularity of the lamina propria, where most collage...

Pediatric Nephrology, 2021

Physiological Reports, 2020

Claudins are a family of tight junction proteins that are expressed during mouse kidney developme... more Claudins are a family of tight junction proteins that are expressed during mouse kidney development. They regulate paracellular transport of solutes along the nephron and contribute to the final composition of the urinary filtrate. To understand their roles during development, we used a protein reagent, a truncated version of the Clostridium perfringens enterotoxin (C‐CPE), to specifically remove a subset of claudin family members from mouse embryonic kidney explants at embryonic day 12. We observed that treatment with C‐CPE decreased the number and the complexity of ureteric bud tips that formed: there were more single and less bifid ureteric bud tips when compared to control‐treated explants. In addition, C‐CPE‐treated explants exhibited ureteric bud tips with larger lumens when compared to control explants (p < .05). Immunofluorescent analysis revealed decreased expression and localization of Claudin‐3, −4, −6, and −8 to tight junctions of ureteric bud tips following treatment with C‐CPE. Interestingly, Claudin‐7 showed higher expression in the basolateral membrane of the ureteric bud lineage and poor localization to the tight junctions of the ureteric bud lineage both in controls and in C‐CPE‐treated explants. Taken together, it appears that claudin proteins may play a role in ureteric bud branching morphogenesis through changes in lumen formation that may affect the efficiency by which ureteric buds emerge and branch.

Pediatric Nephrology, 2019

Bacterial urinary tract infections (UTIs) are one of the most common reasons for children to be a... more Bacterial urinary tract infections (UTIs) are one of the most common reasons for children to be admitted to hospital. Bacteria infect and invade the bladder (the lower urinary tract) and if the infection disseminates to the upper urinary tract, significant inflammation in the kidneys may arise. Inflammation is a double-edged sword: it is needed to clear bacteria, but if excessive, kidney tissue is injured. During injury, nephrons are destroyed and replaced with deposition of extracellular matrix and a renal scar. In this review, we explore the pathogenesis of UTIs and discuss the risk factors that result in dissemination of bladder infection to the kidneys. Three major risk factors predispose to kidney infections: the presence of vesicoureteric reflux, the presence of bladder and bowel dysfunction, and defects in the ability of the host immune response to clear bacteria. In this review, we will discuss these factors, their relationship to renal scarring, and potential treatments that might be beneficial to prevent renal scar formation in children.

American Journal of Physiology-Renal Physiology, 1997

The bone morphogenetic proteins, BMP-2 and OP-1, are candidates for growth factors that control r... more The bone morphogenetic proteins, BMP-2 and OP-1, are candidates for growth factors that control renal branching morphogenesis. We examined their effects in embryonic kidney explants and in the mIMCD-3 cell model of collecting duct morphogenesis (mIMCD-3 cells are derived from the terminal inner medullary collecting duct of the SV40 mouse). Osteogenic protein-1 (OP-1), at a dose of 0.25 nM, increased explant growth by 30% ( P = 0.001). In contrast, 100-fold greater concentrations of OP-1 (28 nM) decreased explant growth by 10% ( P < 0.001). BMP-2 was entirely inhibitory (maximum inhibition of 7% at 5 nM, P < 0.0004). In an in vitro model for branching morphogenesis utilizing the kidney epithelial cell line, mIMCD-3, low doses of OP-1 (<0.5 nM) increased the number of tubular structures formed by 28 ± 5% ( P = 0.01), whereas concentrations >0.5 nM decreased that number by 22 ± 8% ( P = 0.02). All concentrations of BMP-2 (0.05–10 nM) were inhibitory (maximum inhibition at 1...

European journal of medical genetics, Jan 31, 2018

Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fet... more Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants. The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD, which points to a role of the renin-angiotensin system in gut development.

Kidney International, 2017

American journal of physiology. Renal physiology, Jan 19, 2017

Osr1 is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem... more Osr1 is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesico-ureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter resulting in a less competent uretero-vesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse. OSR1 was sequenced in one hundred and eighty-six children with primary vesico-ureteric reflux and seventeen have single nucleotide polymorphisms. Fifteen children have a common synonymous variant, rs12329305, one child has a rare non-synonymous variant, rs3440471, and one child has a rare 5'UTR variant, rs45535040. The impact of these SNPs is not clear, therefore, the role of OSR1 in huma...

The Faseb Journal, Apr 1, 2011

Pediatric Nephrology, 2016