Microalbuminuria in Type 1 Diabetes Is Associated With Enhanced Excretion of the Endocytic Multiligand Receptors Megalin and Cubilin

Thrailkill, Kathryn M.; Nimmo, Teresa; Bunn, R. Clay; Cockrell, Gael; Moreau, Cynthia; Mackintosh, Samuel G.; Edmondson, Ricky D.; Fowlkes, John L.

doi:10.2337/dc09-0112

Cited by 97 publications

(77 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…31,32 In humans, shedding of megalin and cubilin in urine is increased in individuals with type 1 diabetes and microalbuminuria compared with nonalbuminuric controls. 33 These studies suggest that reduced expression or loss of the cubilin-megalin complex may contribute to the albuminuria of early diabetic kidney disease via reduced tubular reuptake of filtered albumin, which is supported by our observed association of rs1801239 with incident persistent microalbuminuria in the DCCT/EDIC Study.…”

Section: Discussionsupporting

confidence: 74%

CUBN Is a Gene Locus for Albuminuria

Böger¹,

Chen²,

Tin³

et al. 2011

Journal of the American Society of Nephrology

213

210

View full text Add to dashboard Cite

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P ϭ 1.1 ϫ 10 Ϫ11) and microalbuminuria (P ϭ 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

show abstract

Section: Discussionsupporting

confidence: 74%

CUBN Is a Gene Locus for Albuminuria

Böger¹,

Chen²,

Tin³

et al. 2011

Journal of the American Society of Nephrology

213

210

View full text Add to dashboard Cite

show abstract

“…We measured urinary albumin for two purposes. 1) albumin, like DBP, is a known ligand of megalin (30), and 2) severe albuminuria is a biological marker of nephropathy (8,30,31). We found that marked albuminuria was present in the ZDF animals, which excreted ϳ20-fold greater amounts of albumin compared with lean control animals.…”

Section: Study 1: Characterization Of Renal Vitamin D Reabsorption Inmentioning

confidence: 57%

“…In support of this concept, researchers showed that when megalin, cubilin, or Dab2 expression is absent, loss of 25D 3 -DBP in the urine was dramatically elevated and severe vitamin D deficiency resulted (21,22). Moreover, renal megalin and cubilin levels were markedly reduced in humans and rats with diabetes (30,31), which resulted in increased urinary excretion of albumin, another known ligand of megalin.…”

mentioning

confidence: 79%

Vitamin D homeostasis is compromised due to increased urinary excretion of the 25-hydroxycholecalciferol-vitamin D-binding protein complex in the Zucker diabetic fatty rat

Anderson

Ternes²,

Strand³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

[1,25-dihydroxycholecalciferol (1,25D 3)] have been linked to non-insulin-dependent diabetes mellitus (NIDDM). However, a mechanistic basis for this occurrence has not been fully elucidated. Normally, renal reabsorption of vitamin D-binding protein-bound 25D 3 absolutely requires receptor-mediated endocytosis via a receptor complex containing megalin, cubilin, and disabled-2 (Dab2), whereas an absence of megalin or its endocytic partners can lead to a marked urinary loss of 25D and severe vitamin D deficiency. Therefore, we hypothesized that reduced serum vitamin D status in NIDDM may be due to reduced expression of megalin and/or its endocytic partners and increased urinary excretion of protein-complexed 25D 3. In the present study, we utilized Zucker diabetic fatty Rats (ZDF) to demonstrate that renal reuptake of the 25D 3-DBP complex was compromised in ZDF animals, which was reflected by a reduction in expression of megalin and Dab2. Moreover, serum levels of both 25D 3 and 1,25D3 were reduced, and urinary 25D 3, 1,25D3, and DBP excretion were elevated in the ZDF animals compared with their lean controls regardless of vitamin D levels in the diet. Taken together, these are the first reports to our knowledge that associate compromised renal reabsorption of the 25D3-DBP complex with expression of megalin and its endocytic partners in NIDDM, which in turn can lead to compromised vitamin D status. diabetes; kidney OPTIMAL VITAMIN D STATUS HAS BEEN ASSOCIATED with improved long-term health outcomes in cardiovascular disease and cancer, complications that occur at higher incidences in individuals with non-insulin-dependent diabetes mellitus (NIDDM). Poor renal function, also a consequence of poorly controlled type 2 diabetes, results in hypertension, increased epithelial cell damage, and increased risk for cardiovascular disease (3,11). In addition to data from case control studies that indicates that maintenance of optimal serum 25-hydroxycholecalciferol (25D 3 ) concentrations (Ͼ90 nmol/l) is preventative against many types of cancer, research has suggested that optimal vitamin D status may be protective against hypertension and nephron damage through the suppression of renin production in the kidney (13, 36). Furthermore, clinical and epidemiological studies have suggested that type 2 diabetics and individuals with chronic kidney disease are more likely to be in what is considered the suboptimal range (Ͻ80 nmol/l) with respect to serum vitamin D status (7, 15), although the mechanistic basis for this occurrence has not been elucidated. Therefore, fully understanding all factors influencing vitamin D homeostasis in this population may reveal opportunities to improve outcomes and comorbidities associated with type 2 diabetes, especially those with renal complications.Cells of the renal proximal tubule are responsible for reabsorption of the major circulating form of vitamin D (25D 3 ) from the glomerular filtrate and are the primary site of activation of 25D 3 to the active hormone 1,25-dihydroxycholecalciferol ...

show abstract

“…87 Patients with type 1 diabetes and albuminuria had significantly elevated urinary levels of megalin and cubilin, suggesting possible PT shedding of these proteins as a contributing factor to albuminuria in patients with diabetes. 88 Moreover, in early streptozotocin-induced diabetes in rats, the GSC A was unchanged but PTC uptake of albumin was markedly reduced. 47 …”

Section: The Megalin-cubilin Complexmentioning

confidence: 97%

The Proximal Tubule and Albuminuria

Dickson

Wagner

Sandoval

et al. 2014

Journal of the American Society of Nephrology

231

227

View full text Add to dashboard Cite

Recent data highlight the role of the proximal tubule (PT) in reabsorbing, processing, and transcytosing urinary albumin from the glomerular filtrate. Innovative techniques and approaches have provided exciting insights into these processes, and numerous investigators have shown that selective PT cell defects lead to significant albuminuria, even reaching nephrotic range in animal models. Thus, the mechanisms of albumin reabsorption and transcytosis are undergoing intense study. Working in concert with megalin and cubilin, a nonselective multireceptor complex that predominantly directs proteins for lysosomal degradation, the neonatal Fc receptor (FcRn) located at the brush border of the apical membrane has been implicated as the "receptor" mediating albumin transcytosis. The FcRn pathway facilitates reabsorption and mediates transcytosis by its pH-dependent binding affinity in endosomal compartments. This also allows for selective albumin sorting within the PT cell. This reclamation pathway minimizes urinary losses and catabolism of albumin, thus prolonging its serum half-life. It may also serve as a molecular sorter to preserve and reclaim normal albumin while allowing "altered" albumin to be catabolized via lysosomal pathways. Here, we critically review the data supporting this novel mechanism. Although the importance of urinary albumin in disease progression is known, the key mechanisms mediating the presence and toxic effects of albuminuria remain to be determined. Recently, the quantitative role of the glomerular filtration barrier (GFB) and the proximal tubule (PT) cell (PTC) in the development of albuminuria has been reexamined. Different lines of evidence, from multiple investigative teams, now suggest that the filtration of albumin, under physiologic conditions, is greater than previously determined. These data suggest an increased clinical role for the PT in minimizing albuminuria through the reabsorption of albumin. Emerging data also suggest that both glomerular permeability and PTCs play fundamental, physiologic, synergistic, interactive, and dynamic roles in the renal handling of albumin. Furthermore, it appears that PTCs, especially in the S1 segment, have specific mechanisms for efficiently and effectively reabsorbing and transcytosing albumin (reclamation). Therefore, the purpose of this review is to describe the emerging data regarding PTC albumin handling and provide a framework for considering future exciting, insightful, and novel studies with direct clinical relevance.This review is not intended to debate the important role of the GFB but to emphasize that the PT should be considered important both under physiologic and pathologic conditions. We believe that glomerular or PTC defects can and do result in proteinuria. Specifically, we outline current data supporting PT uptake of albumin and mechanisms of reabsorption and transcytosis, and we propose a mechanism for intracellular sorting between degradation and transcytotic pathways based on pH-dependent binding. DYSFUNCTIONAL PTCS LE...

show abstract

Microalbuminuria in Type 1 Diabetes Is Associated With Enhanced Excretion of the Endocytic Multiligand Receptors Megalin and Cubilin

Cited by 97 publications

References 14 publications

CUBN Is a Gene Locus for Albuminuria

CUBN Is a Gene Locus for Albuminuria

Vitamin D homeostasis is compromised due to increased urinary excretion of the 25-hydroxycholecalciferol-vitamin D-binding protein complex in the Zucker diabetic fatty rat

The Proximal Tubule and Albuminuria

Contact Info

Product

Resources

About