Impaired Tubular Uptake Explains Albuminuria in Early Diabetic Nephropathy

Russo, Leileata M.; Sandoval, Ruben M.; Campos, Sílvia B.; Molitoris, Bruce A.; Comper, Wayne D.; Brown, Dennis

doi:10.1681/asn.2008050503

Cited by 233 publications

(265 citation statements)

References 17 publications

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“…Thus, it is comparable to nondiabetic wild type in the 10% hypomorphs, but increases from microalbuminuria to macroalbuminuria as Tgfb1 expression increases from 1/2 to ∼3 times normal. Whether the proteinuria in diabetic nephropathy is due to podocyte/glomerular dysfunction and/or to tubule dysfunction is a subject of debate (21)(22)(23)(24). We found that the albuminuria of the 10% hypomorphs was increased 20 fold by switching Tgfb1 expression from low to high in the tubules, but only fourfold by switching in the podocytes.…”

Section: Discussionmentioning

confidence: 81%

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

Hathaway

Gasim

Grant

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Nephropathy develops in many but not all patients with longstanding type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor β1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2 Akita ). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.aldosterone | glomerular filtration rate | glomerulosclerosis | megalin | nephrin D iabetes is the number one cause of end-stage renal disease in the United States and many other developed countries. However, despite having similar levels of blood glucose only 20-40% of all diabetic patients develop diabetic nephropathy. In diabetic nephropathy, increased expression of transforming growth factor β1 (TGFβ1) has been demonstrated to promote accumulation of extracellular matrix components (1), apoptosis (2), dedifferentiation of podocytes (3), and epithelial-mesenchymal transition of proximal tubules (4), all of which are thought to facilitate a decline in nephron number and renal function.Tgfb1-null mice on a mixed genetic background show severe multiorgan inflammation with massive infiltration of lymphocytes and macrophages that culminates in death by 3-4 wk of age (5, 6). Their death effectively prevents determining whether absence of TGFβ1 influences the development of nephropathy. To overcome this problem and also to allow the study of the effects of above-normal TGFβ1, we have generated mice with five genetically graded levels of TGFβ1, and have made them diabetic with the Ins2 Akita mutation, which causes pancreatic beta-cell dysfunction and type 1 diabetes.Here we show that the features characteristic of diabetic nephropathy are progressively ...

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Section: Discussionmentioning

confidence: 81%

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

Hathaway

Gasim

Grant

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…7 When using two photon microscopy, molecular trans port probes, such as dextrans and Ficolls, of known GSC should, therefore, always be used as standards when measuring albumin GSC. 13 The capacity of the albumin retrieval pathway is so high (~200 g per day) 2 that any malfunction associated with it will result in hypoalbuminaemia. Another feature observed with albumin processing in the kidney is that ~1-2 g of albumin is normally excreted in the urine each day in the form of albumin fragments.…”

Section: Wayne D Compermentioning

confidence: 99%

Albuminuria is controlled primarily by proximal tubules

Comper¹

2014

Nat Rev Nephrol

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“…Alternatively, because the loss of laminin ␣5 from tubular basement membranes (TBMs) appeared more dramatic than the loss from the GBM ( Figure 4F and reference 22), the possibility existed that the proteinuria stemmed in part from tubular cell dysfunction, consistent with concepts proposed by Comper and colleagues. 26,27 To distinguish the pathologic effects of laminin ␣5 reduction in the GBM from those stemming from reduction in TBMs, we devised two different strategies to specifically rescue the Lama5 neo insertion mutation in podocytes. To remove the pathogenic neo insertion specifically in podocytes, we generated transgenic mice designed to express a codon-optimized FLP recombinase (FLPo) 28 under the control of the 4.2-kb mouse nephrin (Nphs1) promoter 29 ( Figure 1B).…”

Section: Podocyte-specific Rescue Of the Lama5 Neo Insertional Mutationmentioning

confidence: 99%

Maintenance of Glomerular Filtration Barrier Integrity Requires Laminin α5

Goldberg¹,

Adair-Kirk

Senior

et al. 2010

Journal of the American Society of Nephrology

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Mutation of the mouse laminin ␣5 gene results in a variety of developmental defects, including defects in kidney structure and function. Whereas the total absence of laminin ␣5 results in breakdown of the glomerular basement membrane (GBM) and failed glomerular vascularization, a hypomorphic Lama5 mutation (the Lama5 neo allele) results in proteinuria, hematuria, polycystic kidney disease (PKD), and death 3 to 4 weeks after birth. Here, we examined the role of podocyte-derived laminin ␣5 via podocyte-specific inactivation of Lama5 and podocyte-specific rescue of the Lama5 neo mutation. Podocyte-specific inactivation of Lama5 resulted in varying degrees of proteinuria and rates of progression to nephrotic syndrome. The GBM of proteinuric mice appeared thickened and "moth-eaten," and podocyte foot processes became effaced. Podocyte-specific restoration of laminin ␣5 production using two distinct strategies in Lama5 neo/neo mice resulted in the resolution of proteinuria, hematuria, and PKD. These results suggest that the development of normal GBM structure and function requires podocytederived laminin ␣5 during and after glomerulogenesis and present a unique mechanism for the pathogenesis of PKD in these mice.

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Impaired Tubular Uptake Explains Albuminuria in Early Diabetic Nephropathy

Cited by 233 publications

References 17 publications

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

Albuminuria is controlled primarily by proximal tubules

Maintenance of Glomerular Filtration Barrier Integrity Requires Laminin α5

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