Kidney cell fate could play key role in regeneration, injury repair

Researchers at the University of Virginia found removal of kidney obstruction promotes regeneration and repair of developing kidneys, which could lead to a better treatment for infants and adults with chronic kidney disease.

“Currently, most severe obstructions (with grade IV hydronephrosis and decreased renal function) are surgically corrected,” Maria Luisa S. Sequeira-Lopez, MD, FAHA, the Harrison Distinguished Professor in Pediatrics and Biology at University of Virginia and co-author of the study, said. “Babies with mild to moderate obstructions are followed with ultrasound, and renal function tests and surgical intervention is indicated when renal function decreases more or if the hydronephrosis progresses. However, based on our studies in mice, early removal of the obstruction may prevent further kidney damage.”

Sequeira-Lopez and colleagues used a partial unilateral obstruction model in genetically modified neonatal mice, which mimicked congenital ureteropelvic junction (UPJ) obstruction, to better understand the capacity of the kidney at the early stage for recovery and regeneration after surgical release of obstruction. To understand the role of changing cell fate, they traced the fate of various progenitor cells of the kidney.

Vascular precursors linked to regeneration

Investigators found the release of obstruction led to “striking regeneration of tubules, arterioles [and] interstitium accompanied by an increase in blood flow,” the authors wrote.

Researchers identified both the major renal progenitor cells that contribute to kidney damage during obstruction and those that contribute to regeneration after its release. Foxd1-positive cells, the precursors for all mural cells in the vasculature, were shown to be of particular importance, as the regeneration of vasculature was found to promote renal blood flow.

“The marked regeneration of the kidney’s arterial tree after the release of obstruction in our mouse model strongly suggests that vascular precursors are still able to differentiate into vessels of different caliber/function [in infants] ... Upon release of obstruction, we saw a remarkable regeneration of the vasculature accompanied by tubular regeneration and interstitial repair,” Sequeira-Lopez said. “The study strongly suggests that the kidney vasculature plays a direct and central role in the ability of the kidney to regenerate and repair after injury and highlights the importance of surgical intervention.”

The researchers believe this regeneration was due to a decrease in hypoxia, renal oxidative stress and mitochondrial and fatty acid oxidation dysfunction.

Sequeira-Lopez added the results also indicate working to maintain a healthy renal vasculature and/or promoting its regeneration “will be a major step to prevent the loss of kidney function associated with many kidney diseases.”

Another interesting finding that occurred before removal of obstruction was the change in the undamaged kidney, which enlarged in proportion to the severity of damage in the obstructed kidney.

“It was as if the undamaged kidney regenerates to compensate for the extent of loss in the damaged one. We saw a notable increase in the vascular structure in the right kidney. More work is needed to further understand the phenomenon of ‘compensatory hypertrophy’ in the [undamaged] kidneys,” Sequeira-Lopez said.

‘Critical time window’

The investigators found timing of the release of obstruction greatly impacted recovery with animals categorized on a hydronephrosis index of severity, more than 96% of kidneys with moderate hydronephrosis recovered near-normal architecture, while 36% of kidneys with severe hydronephrosis recovered. The results indicate surgical correction of congenital obstruction nephropathy should take place as soon as possible.

“We think that during kidney injury there is a critical time window, and the necessary intervention is needed before this time window elapses,” Sequeira-Lopez said. “Cell fate may not be reversed after a certain point of damage, as in the case of severe injury; whereas, when the damage is moderate, the fate of cells may still be changed or reversed upon removal of obstruction.”

Sequeira-Lopez said a better understanding of the cellular and molecular regulators of cell fate after release of kidney obstruction could eventually help researchers to reprogram cells that are severely damaged.

The findings suggest that developing kidneys have significantly higher potential to recover renal vasculature than adult kidneys, but the researchers hope to ultimately discover triggers that can awaken precursors in adult kidneys so that these can regenerate, too.

“Our future studies are aimed at defining the molecular mechanisms and regulators involved in the regeneration of the kidney vasculature and the interaction with the renal parenchyma during repair. Ultimately, we would like to harness this knowledge to identify therapeutic targets to treat children and adults suffering from chronic kidney disease,” Sequeira-Lopez said.– by Amanda Alexander

Reference:

Nagalakshmi V. K, et al. Clinical Science. 2018;doi:10.1042/cs20180623.

Disclosures: The authors report the study was supported by the NIH.