There is little experimental study on the effects of mechanical forces, especially elevated hydrodynamic pressure on tubular cell biology. Recently, some evidence has emerged that increased pressure alters some aspects of the gene expression programme consistent with a pro-inflammatory and pro-fibrogenic change in tubular cell phenotype.
Broadbelt et al. The observations cited earlier in this narrative that pressure and stretch dilatation in osmotic diuresis are greatest in the distal nephron, mainly the collecting duct, may account for the observation that these dilated portions of the nephron in experimental diabetes express increased levels of fibrosis-regulating proteins rather than other portions of the nephron that are exposed to the same level of ambient glycemia and glycated proteins.
In addition to distal nephron dilatation and stretch, and elevated luminal pressure, tubular cells are also exposed to a second physical force that results from the increased nephron flow in osmotic polyuria of diabetes, namely shear stress.
There is a large body of literature on the effects of shear stress on the vasculature and on endothelial cells demonstrating important effects on the cytoskeleton, cell signals and gene expression, but little is known about the effects of this mechanical force on tubular cells. Nevertheless, there is evidence from recent experimental observations that tubular cells in vivo and in vitro recognize and respond to fluid flow velocity and the associated shear stress.
It is noteworthy that in experimental diabetes in rats proximal tubular microvilli height is significantly reduced, perhaps in response to the constant exposure to increased tubular fluid flow rates [ 25 ].
In cultured tubular cells transient exposure to shear stress at the apical membrane induces a substantial re-arrangement of the actin cytoskeleton.
In this experiment shear stress is also associated with increased transcription factor binding to the shear stress response element SSRE , suggesting changes in the regulation of gene expression that may not be dissimilar to those that occur in shear stress-challenged endothelial cells [ 8 ].
In collecting duct cells, increased shear stress raises nitric oxide release suggesting activation of one or more NOS-isoforms [ 3 ]. Overall, experimental findings showing that mechanical forces luminal pressure and shear stress cause alterations in tubular cell phenotype and their gene expression program is highly compatible with in vivo observations that increased the expression of pro-inflammatory and pro-fibrogenic regulators occur in dilated distal nephron segments in diabetic nephropathy.
In summary, in the present narrative we review observational evidence supporting an important role of tubular fluid pressure and flow dynamics as additional cause of early tubular cell injury in diabetic renal interstitial nephropathy. Increased tubular pressure and shear stress occur especially in the distal nephron collecting ducts as a result of hyperglycaemic osmotic polyuria due to poorly controlled diabetes.
Evidence suggests that these mechanical forces are important but overlooked mechanisms contributing to the induction and progression of tubulo-interstitial fibrogenesis in diabetic nephropathy. Google Scholar. Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Osmotic polyuria: an overlooked mechanism in diabetic nephropathy. Shinong Wang , Shinong Wang.
Oxford Academic. Grace M. Raimund Hirschberg. Select Format Select format. Permissions Icon Permissions. Abstract Tubulo-interstitial pathology in diabetic nephropathy is thought to be caused by cell injury that is induced by high ambient glucose levels and increased proportions of glycated proteins. Diabetes , diabetic nephropathy , polyuria , shear stress , tubular pressure. Open in new tab Download slide.
The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of cases of diabetic glomerulosclerosis. Google Scholar Crossref.
Search ADS. Shear stress-mediated NO production in inner medullary collecting duct cells. Google Scholar PubMed. Cyclo-oxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Functional and structural changes in the rat kidney by long-term lithium treatment. Mechanical strains induced by tubular flow affect the phenotype of proximal tubular cells.
Delivery and expression of fluid shear stress-inducible promoters to the vessel wall: applications for cardiovascular gene therapy. Tubular expression of connective tissue growth factor correlates with interstitial fibrosis in type 2 diabetic nephropathy.
Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease. Effects of diuretic states on collecting duct fluid flow resistance in the hamster kidney. Renal histologic and ultrastructural findings in psychogenic polydipsia and diabetes insipidus. Prevention of diabetic glomerulopathy in streptozotocin diabetic rats by insulin treatment. Kidney size and glomerular volume. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice.
Application of red laser video-rate scanning confocal microscopy to in vivo assessment of tubular function in the rat: selective action of diuretics on tubular diameter. Glomerular filtration and tubular reabsorption of albumin in preproteinuric and proteinuric diabetic rats. The structure of the glomerular capillary basement membrane in diabetes mellitus with and without nephrotic syndrome. Ontogeny of flow-stimulated potassium secretion in rabbit cortical collecting duct: functional and molecular aspects.
All rights reserved. For Permissions, please e-mail: journals. Issue Section:. Download all slides. Comments 0. Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel. Submit a comment. Comment title. You have entered an invalid code. Submit Cancel. Thank you for submitting a comment on this article.
Your comment will be reviewed and published at the journal's discretion. Please check for further notifications by email. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. Related articles in Web of Science Google Scholar. Citing articles via Web of Science The management of membranous nephropathy — an update. We value your privacy. When you visit JDRF.
I Decline I Agree. Polyuria and Type 1 Diabetes Type 1 diabetes is an autoimmune disease that causes your pancreas to stop producing insulin, a hormone that is essential to getting energy from food. What causes frequent urination with diabetes? Be the first to know about T1D news, local events and more. This field is for validation purposes and should be left unchanged. Sign Up. Also of Interest:.
0コメント