Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Vegt, Erik; Melis, Marleen; Eek, Annemarie; Visser, Maartje De; Brom, Maarten; Oyen, Wim J.G.; Gotthardt, Martin; Jong, Marion de; Boerman, Otto C.

doi:10.1007/s00259-010-1685-9

Cited by 110 publications

(107 citation statements)

References 32 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is known that small peptides are filtered by glomerular filtration, but can be reabsorbed by endocytic receptors in proximal tubular cells, notably megalin. The exact mechanisms by which the B1R peptides presented in this study accumulate in the kidneys remain unknown, but likely follow similar mechanisms (18).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer

et al. 2015

View full text Add to dashboard Cite

The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by PET. Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids ( 68 Ga-SH01078 and 68 Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues, and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor mediated. Our results offer a preclinical proof of concept for noninvasive B1R detection by PET imaging as a general tool to visualize many human cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…[39][40][41] Kidney sections from bardoxolone methyl-treated monkeys demonstrated decreased megalin protein expression ( Figure 1A) despite similar mRNA expression across groups (data not shown). The visualized decrease in megalin protein expression was confirmed by densitometry analyses, which demonstrated that bardoxolone methyl administration significantly decreased megalin protein expression in the monkey kidney ( Figure 1B).…”

Section: Bardoxolone Methyl Decreases Renal Expression Of Megalin Butmentioning

confidence: 99%

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Reisman

Chertow

Hebbar

et al. 2012

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD. Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum phosphorus, and uric acid concentrations in patients with moderate to severe CKD. However, it also increases albuminuria, which is associated with inflammation and disease progression. Therefore, we investigated whether this bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipid-bound proteins. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlated with the urine albuminto-creatinine ratio. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum creatinine and BUN, as observed in patients with CKD. Finally, the bardoxolone methyl-induced decrease in megalin corresponded with pharmacologic induction of renal Nrf2 targets, including NAD(P)H:quinone oxidoreductase 1 enzyme activity and glutathione content. This result indicates that Nrf2 may have a role in megalin regulation. In conclusion, these data suggest that the increase in albuminuria that accompanies bardoxolone methyl administration may result, at least in part, from reduced expression of megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets. 23: 166323: -167323: , 201223: . doi: 10.1681 Pathogenic stimuli in patients with CKD and type 2 diabetes, including hypertension, obesity, heightened renin-angiotensin activity, and albuminuria, activate oxidative stress-mediated inflammation. [1][2][3][4][5] Indeed, oxidative stress and impaired antioxidant capacity intensify with progression of CKD, 6,7 and production of reactive oxygen species and oxidative stress result in activation of the transcription factor nuclear factor kB (NFkB). NFkB regulates expression of proinflammatory cytokines and chemokines, and its pathologic activation is a hallmark of many inflammatory disorders, including CKD. Activated NFkB is present in the kidneys of patients with diabetic nephropathy but is undetectable in normal healthy kidneys. 8 Thus, oxidative stress facilitates proinflammatory signaling, which frequently results in further oxidative stress, thereby creating a destructive feedback loop and, often, perturbation of normal physiologic processes and disease progression. J Am Soc NephrolTo respond to oxidative and electrophilic stimuli, organisms have developed elaborate cytoprotective pathways that are directly regulated by the

show abstract

“…10 Moreover, a profound decrease in radioactivity accumulation in the kidneys of megalin-deficient mice was observed for several radiolabeled small peptides, thus clearly indicating direct involvement of the megalin/cubilin system in the reabsorption process of these agents. 11 Accumulation of the radiotracer in the kidney by the megalin/cubilin system is a complex process. Megalin is a large multi-ligand receptor (517 kDa) with several domains, each of which might interact with different parts of the ligand.…”

Section: Introductionmentioning

confidence: 99%

In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors

Altai

Varasteh

Andersson

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

Self Cite

View full text Add to dashboard Cite

Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z HER2:342 was developed for imaging of HER2 expression in tumors and a clinical study has demonstrated that the 111 In-and 68 Ga-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, significant renal accumulation of radioactivity after systemic injection of radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in murine model and in vitro using opossum derived proximal tubule cells (OK). It was found that kidney reabsorption of affibody was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody were involved in binding to OK cells. On OK cells two types of receptors for anti-HER2 affibody were found: K D1 =0.8 nM, B max1 =71,500 and K D2 =9.2 nM, B max2 =367,000. The results of the present study indicate affibody and other scaffold-based targeting proteins with relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

show abstract

Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Cited by 110 publications

References 32 publications

In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer

In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors

Contact Info

Product

Resources

About