(From the January 2015 Issue of Research Now)
Carbonic anhydrase 2 (Car2), an enzyme essential to maintaining the balance of acids and bases in the kidney, is part of the innate defense of the kidney, according to a study performed by clinician-scientists at Nationwide Children’s Hospital and collaborating institutions. Once the enzymes and proteins involved in infection susceptibility are further defined, the researchers say, they could be up- or down-regulated to influence the kidneys’ ability to ward off infection, improving the body’s ability to defend itself without antibiotics.
“We studied the role of carbonic anhydrase 2 because it is needed for the kidneys to control acid-base status,” says Andrew Schwaderer, MD, research director of Nephrology at Nationwide Children’s and senior author on the study, which was published in October 2014 in the American Journal of Physiology: Renal Physiology. “Increasing evidence also indicates that acid-base balance and immune function are linked.”
The team evaluated the biological consequences of a Car2 deficiency in a murine model of a specific type of kidney infection, known as pyelonephritis. They found that Car2-deficient mice had increased burdens of kidney bacteria along with decreased ability to clear bacteria from the kidneys, compared to their counterparts without the Car2 deficiency. The Car2-deficient mice also showed abnormalities in mRNA and proteins related to immune response and a profoundly impaired ability to upregulate key bacterial response genes.
According to Dr. Schwaderer, the findings provide the first evidence of Car2 and intercalated cells’ involvement in promoting renal bacterial clearance in vivo, or within a living organism. Intercalated cells are one of the two cell types that comprise the collecting duct system of kidneys. As expression of Car2 decreased, antimicrobial peptide production by cells other than kidney intercalated cells increased. Antimicrobial peptides have been shown to be key actors in the urinary tract’s innate immune system, with a potent ability to kill infectious microorganisms and defend the kidneys against infection.
This increase in antimicrobial peptide production did not protect Car2-deficient mice when challenged with uropathogenic bacteria, however. Even after re-normalizing urine pH (a measure of acidity or basicity) and serum bicarbonate levels (a measure of acidity in the blood) in the mice, susceptibility to kidney infection did not return to normal. Researchers found that Car2-deficient mice were still at an increased risk of pyelonephritis.
“If you manipulate enzymes involved in acid-base balance, you alter infection susceptibility even if you normalize the pH,” Dr. Schwaderer says. “This suggests a larger role for Car2 and intercalated cells in promoting renal bacterial clearance than we previously appreciated.”
Although the murine studies offered excellent insight into the mechanisms at play in the kidneys’ susceptibility to infection, further research will be needed to uncover Car2’s importance in human pyelonephritis patients. “We are currently evaluating acid-base balance and immune function in humans,” says Dr. Schwaderer, who also is a principal investigator in the Center for Clinical and Translational Research in The Research Institute at Nationwide Children’s and an associate professor of pediatrics at The Ohio State University College of Medicine.
The team hopes that elucidation of the roles of the enzymes and proteins in pyelonephritis might have direct implications for clinical care. “It might eventually be possible,” Dr. Schwaderer says, “to increase or decrease the immune system’s function by altering the levels of proteins involved in acid-base balance.”
Hains DS, Chen X, Saxena V, Barr-Beare E, Flemming W, Easterling R, Becknell B, Schwartz GJ, Schwaderer AL. Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility. American Journal of Physiology: Renal Physiology. 2014 Aug 20. [Epub ahead of print]