Renal interstitial hyaluronan: functional aspects during normal and pathological conditions

Abstract

<jats:p>The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physicochemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the background of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.</jats:p>

Marked Elevation of Serum Hyaluronan Levels in Collagenofibrotic Glomerulopathy

“…Therefore, we evaluated hyaluronan deposition with colloidal iron staining before and after hyaluronidase digestion. Colloidal iron staining is widely used to detect negatively charged surface matrices, and the interstitium generally contains large quantities of negatively charged glycosaminoglycans, such as hyaluronan (11). Moreover, glomerular capillary surfaces are covered by podocytes, which have anionic glycocalyx layers (12).…”

Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

“…160 The production of another proinflammatory molecule (i.e., HA) is also induced by hyperglycemia through a protein kinase C/TGF-b pathway. 163 Besides HA, several DAMPs, including the glucose-inducible HMGB1, 164 biglycan, and decorin, are overexpressed in diabetic kidneys and may trigger inflammation by activating TLR2/TLR4 receptors and NLRP3 inflammasomes. 47,51, 165 Increased renal biglycan levels correlate with enhanced infiltration of macrophages and renal LDL accumulation, and appear to promote kidney injury.…”

“…By contrast, because of its antiapoptotic effects on TECs and ability to neutralize TGF-b1 and CTGF, decorin is nephroprotective in DN. 51 Whereas HA accumulation is considered as a marker of renal damage during DN and is potentially involved in the development of interstitial fibrosis, 163 high molecular weight-HA reduces diabetes-induced renal injury. 32,34,166 Thus, decorin and low molecular weight versus high molecular weight HA, orchestrating signaling of various receptors, appear to act in diabetic kidneys in a scenario more complex than canonical DAMPs.…”

Renal neurohormonal regulation in heart failure decompensation

“…Urea transport through the urea transporter A is important for the concentrating ability by regulating the medullary concentration gradient (14) and is regulated by vasopressin (13), but little is known about the regulation of urea transport in heart failure. Finally, renal medullary hyaluronan counteracts reabsorption by acting as a diffusion barrier in the interstitium and is affected by vasopressin (59). However, its role in heart failureassociated fluid retention is unknown.…”