New discoveries about the HIF-PHD axis may aid efforts to prevent or treat inflammatory bladder injury.

Researchers at Vanderbilt University Medical Center have uncovered new insights into the hypoxia-inducible factor (HIF)-prolyl hydroxylase domain (PHD) axis in inflammatory bladder injury, determining that it could be a target for therapeutic intervention.

The researchers recently published their findings in the American Journal of Physiology-Renal Physiology.

While activation of HIF signaling has been linked to bladder injuries caused by partial outlet obstruction, a leading cause of bladder dysfunction, the role of the HIF-PHD axis in inflammatory bladder injury has remained unclear.

“Knowledge about the role of the HIF-PHD axis in bladder injury is limited, and preclinical studies have produced conflicting results depending upon whether HIF is acutely or chronically activated,” said first author Douglass Clayton, M.D., an associate professor of urology at Vanderbilt.

Under the direction of Volker Haase, M.D., Krick-Brooks Chair in Nephrology and a professor of medicine in the Division of Nephrology and Hypertension at Vanderbilt, Clayton received a K08 career development award to study how pharmacological HIF activation mitigates cyclophosphamide-induced bladder injury and voiding dysfunction. Clayton believes that HIF-activating compounds may prevent or treat bladder injury and urinary dysfunction.

The HIF Pathway

The HIF pathway plays an important role in mucosal barrier function immune responses and promotes epithelial survival during periods of cellular stress. The pathway is highly conserved across eukaryotic organisms and is critical for cellular adaptation to hypoxic stress, the researcher explained.

“Conventional therapies for treating severe bladder inflammation can defunctionalize the bladder due to fibrosis. Treatments targeting the underlying bladder biology are needed.”

Acute activation of HIF signaling – by either genetic or pharmacological interventions – is believed to prevent organ injury and inflammation.

“Conventional therapies for treating severe bladder inflammation can defunctionalize the bladder due to fibrosis,” Clayton said. “Treatments targeting the underlying bladder biology are needed.”

A Promising Target

According to Clayton, HIF activity is controlled by PHD dioxygenases, which are used as a therapeutic target in the treatment of anemia of chronic kidney disease.

For this study, the researchers showed that two small-molecule inhibitors of HIF-prolyl hydroxylation, dimethyloxalylglycine (DMOG) and molidustat, prevented the damaging effects of cyclophosphamide-induced bladder injury.

In a murine model, this finding was demonstrated by the preservation of normal bladder morphology and urothelial integrity, reduction in bladder cytokine levels, and maintenance of normal voiding patterns.

In patients receiving cyclophosphamide, the production of the metabolite acrolein can lead to severe bladder injury, and in some cases, require cystectomy. Although some treatments are available, these interventions alone are not effective in all patients and alternative strategies are needed for the prevention of cyclophosphamide-induced bladder injury.

More Studies Ahead

Clayton says the exact mechanisms that underpin the HIF-PHD axis in protecting the bladder remain undiscovered, but he believes PHD efficacy most likely involves improved urothelial cell survival and barrier function, which prevents exposure and injury from acrolein.

As a result, the study findings are likely to provide a strong basis for future mechanistic studies, noting that this may be an important area of clinical relevance, as many patients present after the onset of injury.

“We hope that, in the future, specific investigations will be undertaken to unravel the complexities of these pathways and cell types,” Clayton said. “HIF-prolyl hydroxylase inhibitors could be a new clinically relevant therapeutic lead for patients with these injuries.”

About the Expert

Douglass Clayton, M.D.

Douglass Clayton, M.D., is an associate professor of urology in Vanderbilt University Medical Center’s Division of Pediatric Urology. His care emphasizes management of children with myelomeningocele, the fetal diagnosis of urologic anomalies, and minimally invasive surgeries. His research interest is the role of hypoxic signaling in the bladder and the therapeutic effects of acute activation of the hypoxia inducible factor pathway in the bladder.