Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration

Abstract

Background. Hyaluronan (HA) is the dominant glycosaminoglycan in the renomedullary interstitium. Renomedullary HA has been implicated in tubular fluid handling due to its water-attracting properties and the changes occurring in parallel to acute variations in the body hydration status.Methods. HA production was inhibited by 4-methylumbelliferone (4-MU in drinking water for 5 days, 1.45 ± 0.07 g/day/kg body weight) in rats prior to hydration.Results. Following hypotonic hydration for 135 min in control animals, diuresis and osmotic excretion increased while sodium excretion and glomerular filtration rate (GFR) remained unchanged. The medullary and cortical HA contents were 7.85 ± 1.29 ng/mg protein and 0.08 ± 0.01 ng/mg protein, respectively. Medullary HA content after 4-MU was 38% of that in controls (2.98 ± 0.95 ng/g protein, p < 0.05), while the low cortical levels were unaffected. Baseline urine flow was not different from that in controls. The diuretic response to hydration was, however, only 51% of that in controls (157 ± 36 versus 306 ± 54 µl/g kidney weight/135 min, p < 0.05) and the osmolar excretion only 47% of that in controls (174 ± 47 versus 374 ± 41 µOsm/g kidney weight/135 min, p < 0.05). Sodium excretion, GFR, and arterial blood pressure were similar to that in control rats and unaltered during hydration.Conclusions. Reduction of renomedullary interstitial HA using 4-MU reduces the ability of the kidney to respond appropriately upon acute hydration. The results strengthen the concept of renomedullary HA as a modulator of tubular fluid handling by changing the physicochemical properties of the interstitial space.

A role for the extracellular matrix component hyaluronan in kidney dysfunction during ACE‐inhibitor fetopathy

“…, Stridh et al . ). Hormones such as vasopressin, Ang II, prostaglandins, nitric oxide and endothelin‐1 change the turnover of HA, inferring a physiological relevance of HA in the regulation of renal fluid handling.…”

“…Pharmacological inhibition of HA synthesis in the normal rat reduces the ability of the kidney to respond with an appropriate diuretic response upon hydration (Stridh et al . ). Furthermore, such inhibition during renal ischaemia–reperfusion injury improves kidney function considerably (Colombaro et al .…”

“…Reduction of medullary HA using HA synthesis inhibition in the normal rat disables a normal diuretic response to hydration (Stridh et al . ). In the rat, this heterogenous distribution is established postnatally, that is during the first 3 weeks after birth, corresponding to late nephrogenesis (Belsky & Toole , Nilsson et al .…”

In vitroanalysis of 4-methylumbelliferone as a sole carbon source forLactobacillus helveticus2126

“…Thus, the long‐term treatment with 4‐MU is anticipated to cause problems with chemotherapies that are renally cleared (Stridh et al . ). It is expected that targeting conditions in liver and intestine will be less problematic due to much higher exposures experienced in these organs after oral dosing (Nagy et al .…”

“…It was observed that in mouse models, 4-MU was associated with reduced electrolyte and fluid excretion in response to rapid hydration (Yoshihara et al 2005). Thus, the long-term treatment with 4-MU is anticipated to cause problems with chemotherapies that are renally cleared (Stridh et al 2013). It is expected that targeting conditions in liver and intestine will be less problematic due to much higher exposures experienced in these organs after oral dosing (Nagy et al 2015).…”