Why Do We Not All Have Proteinuria? An Update of Our Current Understanding of the Glomerular Barrier

Haraldsson, Börje; Sörensson, Jenny

doi:10.1152/nips.01461.2003

Cited by 79 publications

(84 citation statements)

References 18 publications

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“…More recently, focus has shifted to the podocytes, since several novel proteins in the podocyte slit diaphragm have been found to be important for the barrier function [1][2][3]. In addition, we have suggested a role for the glomerular endothelial cell glycocalyx [4][5][6][7][8][9][10], an idea supported also by others [11,12].…”

Section: Introductionsupporting

confidence: 73%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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Aims/hypothesis Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size-or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks. Materials and methods During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8°C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications. Results At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 Å with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes. Conclusions/interpretation We conclude that glomerular charge-but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

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Section: Introductionsupporting

confidence: 73%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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“…The unmodified antibodies, an scDb of 55 kDa and an scFv of 28 kDa, were rapidly cleared from circulation with terminal half-lives of 1.3 h for the scDb and 0.6 h for the scFv. In a previous study of the same scDb used here, we showed that this is mainly due to rapid renal clearance (22), reflected also by the Stokes radius of only 2.6 nm, which allows almost unhindered passage through the glomerular filtration barrier (23). Only marginal effects on the half-life was seen for the SpA EZ4 and the PpL C4 * fusion proteins with 2-3-fold increased half-lives.…”

Section: Discussionmentioning

confidence: 52%

Plasma Half-life Extension of Small Recombinant Antibodies by Fusion to Immunoglobulin-binding Domains

Hutt

Färber-Schwarz

Unverdorben

et al. 2012

Journal of Biological Chemistry

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Background: Half-life extension has become increasingly important for therapeutic proteins. Results: Fusion of different bacterial immunoglobulin-binding domains to small recombinant antibodies prolonged their half-life to varying extents. Conclusion: Fusion of domain C3 of streptococcal protein G showed the best effects, thus representing a promising module for half-life extension of small-sized therapeutics. Significance: This study further established immunoglobulin-binding domains as suitable half-life extension modules.

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“…Recently, we developed a novel leptin version by fusing a polypeptide comprising 600 Pro, Ala and Ser (PAS) residues to the N-terminus of the murine protein [11]. The PAS moiety adopts a random coil conformation and expands the average diameter of the fusion protein beyond the pore size of the kidney filtration barrier [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

et al. 2016

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Aims/hypothesis Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. Methods A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition.Results In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. Conclusions/interpretation The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.

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Why Do We Not All Have Proteinuria? An Update of Our Current Understanding of the Glomerular Barrier

Cited by 79 publications

References 18 publications

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Plasma Half-life Extension of Small Recombinant Antibodies by Fusion to Immunoglobulin-binding Domains

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

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