IU Indianapolis ScholarWorks :: Browsing by Author "Molitoris, Bruce A."

Browsing by Author "Molitoris, Bruce A."

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A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney
(Springer, 2012) Imamura, Ryoichi; Isaka, Yoshitaka; Sandoval, Ruben M.; Ichimaru, Naotsugu; Abe, Toyofumi; Okumi, Masayoshi; Yazawa, Koji; Kitamura, Harumi; Kaimori, Jyunya; Nonomura, Norio; Rakugi, Hiromi; Molitoris, Bruce A.; Takahara, Shiro; Medicine, School of Medicine
Background: The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO. Methods: To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks. Results: CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis. Conclusion: We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.
Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury
(BioMed Central, 2007-03-01) Mehta, Ravindra L.; Kellum, John A.; Shah, Sudhir V.; Molitoris, Bruce A.; Ronco, Claudio; Warnock, David G.; Levin, Adeera; Medicine, School of Medicine
Introduction Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Methods Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. Results The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. Conclusion We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.
Adenoviral Vectors Expressing Human Endostatin–Angiostatin and Soluble Tie2: Enhanced Suppression of Tumor Growth and Antiangiogenic Effects in a Prostate Tumor Model
(Elsevier, 2005-12-01) Raikwar, Sudhanshu P.; Temm, Constance J.; Raikwar, Nandita S.; Kao, Chinghai; Molitoris, Bruce A.; Gardner, Thomas A.; Urology, School of Medicine
Angiogenesis is essential for prostate cancer development and metastasis. Antiangiogenic therapy targeting tumor neovasculature, therefore, represents a promising approach for prostate cancer treatment. We hypothesized that adenoviral-mediated delivery of a combination of antiangiogenic factors might have an enhanced antitumor response. We developed the adenoviral vectors Ad-hEndo-angio, expressing a unique, chimeric human endostatin–angiostatin fusion protein, and Ad-sTie2, expressing a soluble form of endothelium-specific receptor tyrosine kinase Tie2. Matrigel angiogenesis assays using Ad-hEndo-angio revealed significant inhibition of tubular network formation and endothelial sprouting compared to Ad-sTie2. In vivo studies in a bilateral PC-3 tumor xenograft model following either intratumoral or systemic administration of Ad-hEndo-angio led to enhanced tumor growth suppression compared to Ad-sTie2. A novel finding is that an intratumoral, combination therapy employing one-half the dose of Ad-hEndo-angio as well as Ad-sTie2 led to a complete regression of the injected, as well as the contralateral uninjected, tumor and prolonged the tumor-free survival in 80% of the animals. In addition, a novel, real-time, intravital imaging modality was used to monitor antiangiogenic responses following adenoviral-mediated gene transfer. These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer.
Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications
(American Physiological Society, 2022) Molitoris, Bruce A.; Sandoval, Ruben M.; Yadav, Shiv Pratap S.; Wagner, Mark C.; Medicine, School of Medicine
For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes. Several genetic diseases, nonselective PT cell defects, chronic kidney disease (CKD), and acute PT injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PT injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism, and transcytosis are being reexamined with the use of techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multireceptor complex that mediates albumin binding and uptake and directs proteins for lysosomal degradation after endocytosis. Albumin transcytosis is mediated by a pH-dependent binding affinity to the neonatal Fc receptor (FcRn) in the endosomal compartments. This reclamation pathway rescues albumin from urinary losses and cellular catabolism, extending its serum half-life. Albumin that has been altered by oxidation, glycation, or carbamylation or because of other bound ligands that do not bind to FcRn traffics to the lysosome. This molecular sorting mechanism reclaims physiological albumin and eliminates potentially toxic albumin. The clinical importance of PT albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussion of genetic disorders and therapeutic considerations.
Altered O-glycomes of Renal Brush-Border Membrane in Model Rats with Chronic Kidney Diseases
(MDPI, 2021-10-21) Yu, Aiying; Zhao, Jingfu; Zhong, Jieqiang; Wang, Junyao; Yadav, Shiv Pratap S.; Molitoris, Bruce A.; Wagner, Mark C.; Mechref, Yehia; Medicine, School of Medicine
Chronic kidney disease (CKD) is defined as a decrease in renal function or glomerular filtration rate (GFR), and proteinuria is often present. Proteinuria increases with age and can be caused by glomerular and/or proximal tubule (PT) alterations. PT cells have an apical brush border membrane (BBM), which is a highly dynamic, organized, and specialized membrane region containing multiple glycoproteins required for its functions including regulating uptake, secretion, and signaling dependent upon the physiologic state. PT disorders contribute to the dysfunction observed in CKD. Many glycoprotein functions have been attributed to their N- and O-glycans, which are highly regulated and complex. In this study, the O-glycans present in rat BBMs from animals with different levels of kidney disease and proteinuria were characterized and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). A principal component analysis (PCA) documented that each group has distinct O-glycan distributions. Higher fucosylation levels were observed in the CKD and diabetic groups, which may contribute to PT dysfunction by altering physiologic glycoprotein interactions. Fucosylated O-glycans such as 1-1-1-0 exhibited higher abundance in the severe proteinuric groups. These glycomic results revealed that differential O-glycan expressions in CKD progressions has the potential to define the mechanism of proteinuria in kidney disease and to identify potential therapeutic interventions.
The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration
(American Society for Clinical Investigation, 2019-09-03) Uchida, Masaki; Maier, Bernhard; Waghwani, Hitesh Kumar; Selivanovitch, Ekaterina; Pay, S. Louise; Avera, John; Yun, EJun; Sandoval, Ruben M.; Molitoris, Bruce A.; Zollman, Amy; Douglas, Trevor; Hato, Takashi; Medicine, School of Medicine
Nature exploits cage-like proteins for a variety of biological purposes, from molecular packaging and cargo delivery to catalysis. These cage-like proteins are of immense importance in nanomedicine due to their propensity to self-assemble from simple identical building blocks to highly ordered architecture and the design flexibility afforded by protein engineering. However, delivery of protein nanocages to the renal tubules remains a major challenge because of the glomerular filtration barrier, which effectively excludes conventional size nanocages. Here, we show that DNA-binding protein from starved cells (Dps) — the extremely small archaeal antioxidant nanocage — is able to cross the glomerular filtration barrier and is endocytosed by the renal proximal tubules. Using a model of endotoxemia, we present an example of the way in which proximal tubule–selective Dps nanocages can limit the degree of endotoxin-induced kidney injury. This was accomplished by amplifying the endogenous antioxidant property of Dps with addition of a dinuclear manganese cluster. Dps is the first-in-class protein cage nanoparticle that can be targeted to renal proximal tubules through glomerular filtration. In addition to its therapeutic potential, chemical and genetic engineering of Dps will offer a nanoplatform to advance our understanding of the physiology and pathophysiology of glomerular filtration and tubular endocytosis.
ASN Presidential Address 2013: innovation and individualization--the path forward for nephrology
(American Society for Nephrology, 2014-05) Molitoris, Bruce A.; Department of Medicine, IU School of Medicine
Beyond Biomarkers: Machine Learning in Diagnosing Acute Kidney Injury
(Mayo Clinic, 2019-05) Molitoris, Bruce A.; Medicine, School of Medicine
Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases
(MDPI, 2021-11-11) Yu, Aiying; Zhao, Jingfu; Yadav, Shiv Pratap S.; Molitoris, Bruce A.; Wagner, Mark C.; Mechref, Yehia; Medicine, School of Medicine
Chronic kidney disease (CKD) is defined by a reduced renal function i.e., glomerular filtration rate (GFR), and the presence of kidney damage is determined by measurement of proteinuria or albuminuria. Albuminuria increases with age and can result from glomerular and/or proximal tubule (PT) alterations. Brush-border membranes (BBMs) on PT cells play an important role in maintaining the stability of PT functions. The PT BBM, a highly dynamic, organized, specialized membrane, contains a variety of glycoproteins required for the functions of PT. Since protein glycosylation regulates many protein functions, the alteration of glycosylation due to the glycan changes has attracted more interests for a variety of disease studies recently. In this work, liquid chromatography-tandem mass spectrometry was utilized to analyze the abundances of permethylated glycans from rats under control to mild CKD, severe CKD, and diabetic conditions. The most significant differences were observed in sialylation level with the highest present in the severe CKD and diabetic groups. Moreover, high mannose N-glycans was enriched in the CKD BBMs. Characterization of all the BBM N-glycan changes supports that these changes are likely to impact the functional properties of the dynamic PT BBM. Further, these changes may lead to the potential discovery of glycan biomarkers for improved CKD diagnosis and new avenues for therapeutic treatments.
Chronic endothelin-1 infusion elevates glomerular sieving coefficient and proximal tubular albumin reuptake in the rat
(Elsevier, 2012) Saleh, Mohamed A.; Sandoval, Ruben M.; Rhodes, George J.; Campos-Bilderback, Silvia B.; Molitoris, Bruce A.; Pollock, David M.; Medicine, School of Medicine
Aim: We have previously found that chronic endothelin-1 (ET-1) infusion in Sprague-Dawley rats increases glomerular permeability to albumin (P(alb)) as assessed in vitro independent of blood pressure with no observed albuminuria. In this study, we hypothesized that ET-1 increases glomerular albumin filtration with accompanied increase in albumin uptake via the proximal tubule, which masks the expected increase in urinary albumin excretion. Main methods: Nonfasting Munich-Wistar Fromter rats were surgically prepared for in vivo imaging (n=6). Rats were placed on the microscope stage with the exposed kidney placed in a cover slip-bottomed dish bathed in warm isotonic saline. Rats were then injected i.v. with rat serum albumin conjugated to Texas Red that was observed to enter capillary loops of superficial glomeruli, move into Bowman's space, bind to the proximal tubular cell brush border and reabsorbed across the apical membrane. Glomerular sieving coefficient (GSC) was calculated as the ratio of conjugated albumin within the glomerular capillary versus that in Bowman's space. Rats were again studied after 2 weeks of chronic ET-1 (2 pmol/kg/min; i.v. osmotic minipump). Key findings: Glomerular sieving coefficient was significantly increased in rats following chronic ET-1 infusion (0.025 ± 0.005 vs. 0.017 ± 0.003, p<0.05). Mean fluorescence intensity for conjugated albumin within proximal tubules was increased by ET-1 infusion: 118.40 ± 6.34 vs. 74.27 ± 4.45 pixel intensity (p<0.01). Significance: These data provide in vivo evidence that ET-1 directly increases glomerular permeability to albumin and that albuminuria is prevented by increased PT albumin uptake in the rat.

Browsing by Author "Molitoris, Bruce A."

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