Vasopressin Induces Urinary Uromodulin Secretion By Activating PKA (Protein Kinase A)

Abstract

Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown. Here, we showed that desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. We investigated kidney epithelial cells stably expressing uromodulin to clarify the molecular mechanism. Apical uromodulin secretion was clearly increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on epithelial cell polarity and cyclic AMP-dependent PKA (protein kinase A) signaling pathway. cAMP-mediated activation of proteases was suggested to be involved. In contrast, basolateral secretion of uromodulin was independent of cAMP signaling. Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for urinary tract infections, kidney stones, and potentially hypertension and chronic kidney disease.

Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation

“…Therefore, increased urinary and renal uromodulin levels may be a reasonable response to water deprivation. A previous report demonstrated that mice under short−term treatment with vasopressin, a hormone synthesized in response to dehydration, exhibited increased urinary uromodulin secretion together with reduced intracellular uromodulin levels [ 36 ]. This is, in part, consistent with our results.…”

Uromodulin: more than a marker for chronic kidney disease progression

“…The impact of sex in regulation of uUMOD is also unclear. The uUMOD secretion rate appears to be stable between the sexes [22 ▪ ,23], but some researchers have found higher uUMOD concentrations in males [24], whereas others have not found a difference [17,25]. Most studies identifying regulators of secretion have utilized antibody-based approaches to measure uUMOD levels in various conditions or treatments.…”

Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms

“…Conversely, ADH administration reduces uromodulin secretion and its protein levels in the kidney, although it can acutely cause a burst of urinary release. 36 However, not all studies show a consistent response to ADH or water loading, and this could be related to underappreciated differences in methodology or reporting parameters (Table S1).…”

“…Direct evidence from cell culture data and indirect evidence from observational data support that the basolaterally released uromodulin (and circulating uromodulin, by extension) does not respond to the same stimuli as apically released uromodulin. In particular, the study by Nanamatsu et al 36 showed using a combination of mouse models and in vitro approaches that cyclic AMP-dependent protein kinase A signaling can regulate the release of polymerizing apical but not basolateral uromodulin. In concordance with this, a clinical study showed that correlates of serum and urine uromodulin concentrations differ substantially, thereby also supporting a differential regulation for apical versus basolateral secretion.…”