Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

Vervoort, G.M.M.; Veldman, B.A.J.; Berden, Jo H. M.; Smits, Paul; Wetzels, Jack F.M.

doi:10.1111/j.1365-2362.2005.01497.x

Cited by 72 publications

(58 citation statements)

References 48 publications

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“…Studies in patients with type 1 diabetes support the concept that primary increases in proximal tubular sodium resorption lead to glomerular hyperfiltration through decreased tubulo-glomerular feedback at the macula densa [45]. However, diabetes-induced hyperfiltration has been shown to occur in adenosine A1-receptor-deficient mice, which lack the tubulo-glomerular feedback mechanism [46].…”

Section: Mechanisms Of Hyperfiltration In Diabetesmentioning

confidence: 97%

The clinical significance of hyperfiltration in diabetes

et al. 2010

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Glomerular filtration rate is commonly elevated in early diabetes and patients with this symptom are arbitrarily considered to have hyperfiltration. The prevalence of hyperfiltration in type 1 diabetes varies from less than 25% to more than 75%. The corresponding figures in type 2 diabetes are significantly lower, ranging between 0% and more than 40%. Several factors, methodological and biological, may contribute to the wide variation in estimates of hyperfiltration prevalence. Methodological differences in measurement and evaluation of GFR apply in particular to the handling of plasma disappearance curves of filtration markers. Biological factors that may influence GFR in the hyperfiltration range include glycaemic control, diabetes duration, BMI, sex, pubertal status in type 1 diabetes and age in type 2 diabetes. Hyperglycaemia may influence GFR and albuminuria, and may therefore confound the evaluation of hyperfiltration as an independent risk factor for diabetic nephropathy. Adequate assessment of the relationship between glycaemic control, GFR and AER therefore requires serial measurements of all three variables followed by multivariate analysis. A recent meta-analysis of ten type 1 diabetes studies concluded that the presence of hyperfiltration at baseline more than doubled the risk of developing micro-or macroalbuminuria at follow-up. However, not all studies allowed for confounding factors or regression dilution bias. Future studies will therefore need to address the independent role of hyperfiltration, not only in the evolution of albuminuria, but also in the subsequent decline of GFR.

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Section: Mechanisms Of Hyperfiltration In Diabetesmentioning

confidence: 97%

The clinical significance of hyperfiltration in diabetes

et al. 2010

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“…46 Therefore, the contribution of PGE 2 /EP receptors to changes in salt and water transporters in the PT is of great interest. Our work indicates that PGE 2 increases sodium transporter expression in PT cells via EP 1 -and EP 4 -dependent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Nasrallah

Hassouneh

Zimpelmann

et al. 2015

Laboratory Investigation

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Renal prostaglandin (PG) E 2 regulates salt and water transport, and affects disease processes via EP 1-4 receptors, but its role in the proximal tubule (PT) is unknown. Our study investigates the effects of PGE 2 on mouse PT fluid reabsorption, and its role in growth, sodium transporter expression, fibrosis, and oxidative stress in a mouse PT cell line (MCT). To determine which PGE 2 EP receptors are expressed in MCT, qPCR for EP 1-4 was performed on cells stimulated for 24 h with PGE 2 or transforming growth factor beta (TGFβ), a known mediator of PT injury in kidney disease. EP 1 and EP 4 were detected in MCT, but EP 2 and EP 3 are not expressed. EP 1 was increased by PGE 2 and TGFβ, but EP 4 was unchanged. To confirm the involvement of EP 1 and EP 4 , sulprostone (SLP, EP 1/3 agonist), ONO8711 (EP 1 antagonist), and EP 1 and EP 4 siRNA were used. We first show that PGE 2 , SLP, and TGFβ reduced H 3 -thymidine and H 3 -leucine incorporation. The effects on cell-cycle regulators were examined by western blot. PGE 2 increased p27 via EP 1 and EP 4 , but TGFβ increased p21; PGE 2 -induced p27 was attenuated by TGFβ. PGE 2 and SLP reduced cyclinE, while TGFβ increased cyclinD1, an effect attenuated by PGE 2 administration. Na-K-ATPase α1 (NaK) was increased by PGE 2 via EP 1 and EP 4 . TGFβ had no effect on NaK. Additionally, PGE 2 and TGFβ increased fibronectin levels, reaching 12-fold upon co-stimulation. EP 1 siRNA abrogated PGE 2 -fibronectin. PGE 2 also increased ROS generation, and ONO-8711 blocked PGE 2 -ROS. Finally, PGE 2 significantly increased fluid reabsorption by 31 and 46% in isolated perfused mouse PT from C57BL/6 and FVB mice, respectively, and this was attenuated in FVB-EP 1 null mice. Altogether PGE 2 acting on EP 1 and EP 4 receptors may prove to be important mediators of PT injury, and salt and water transport. Prostaglandin (PG) E 2 is a major product of cyclooxygenase activity in the kidney. It has a substantial role in maintaining hemodynamics, salt and water homeostasis, and affects growth, inflammation, oxidative stress, and fibrotic responses (reviewed in refs. 1-3 ). Four EP receptors (EP 1-4 ) mediate the signalling responses to PGE 2 , by altering intracellular cAMP and/or Ca 2+ levels. Renal cells often simultaneously express multiple EP receptors, and their relative levels determine the cell's response. Although the contribution of the proximal tubule (PT) to overall renal prostaglandin synthesis is minimal, the role of PGE 2 in PT transport function has been considered. For instance, PGE 2 stimulates cAMP and activates protein kinase A, and in turn regulates basolateral organic anion uptake. 4,5 In contrast, long-term exposure to PGE 2 inhibits its excretion by decreasing the levels of basolateral organic anion transporters that are responsible for PGE 2 uptake in rat renal PT cells. 6 The underlying regulatory pathways are not completely understood, but short-term vs long-term exposure to PGE 2 has opposite effects on the overall cell response. PGE 2 also reduces phosphate transpo...

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“…Evidence for a primary hyperreabsorption upstream of the macula densa and a potential role in glomerular hyperfiltration was also obtained in diabetic patients, including studies that showed that fractional proximal reabsorption was elevated and positively correlated with GFR (20,54,162). Increasing the cortical interstitial concentrations of adenosine, which is a mediator of TGF (140), normalizes GFR in STZdiabetic rats (154).…”

Section: Primary Tubular Hyperreabsorption Contributes To Glomerular mentioning

confidence: 99%

The proximal tubule in the pathophysiology of the diabetic kidney

Vallon

2011

American Journal of Physiology-Regulatory, Integrative and Comp

319

306

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Diabetic nephropathy is a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved in the early changes of the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review focuses on the proximal tubule in the early diabetic kidney, particularly on its exposure and response to high glucose levels, albuminuria, and other factors in the diabetic glomerular filtrate, the hyperreabsorption of glucose, the unique molecular signature of the tubular growth phenotype, including aspects of senescence, and the resulting cellular and functional consequences. The latter includes the local release of proinflammatory chemokines and changes in proximal tubular salt and fluid reabsorption, which form the basis for the strong tubular control of glomerular filtration in the early diabetic kidney, including glomerular hyperfiltration and odd responses like the salt paradox. Importantly, these early proximal tubular changes can set the stage for oxidative stress, inflammation, hypoxia, and tubulointerstitial fibrosis, and thereby for the progression of diabetic renal disease.

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Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

Cited by 72 publications

References 48 publications

The clinical significance of hyperfiltration in diabetes

The clinical significance of hyperfiltration in diabetes

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

The proximal tubule in the pathophysiology of the diabetic kidney

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