The Interplay between Histamine H₄ Receptor and the Kidney Function: The Lesson from H₄ Receptor Knockout Mice

Previous studies implicated the histamine H₄ receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H₄ receptor knockout mice (H₄R^-/-). Healthy and diabetic H₄R^-/- mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H₄R^-/- and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H₄R^-/- mice displayed a higher basal glycemia. H₄R^-/- mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H₄R^-/- mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H₄R^-/- mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H₄R^-/- mice. The AQP1 and AQP7 patterns were also different between H₄R^-/- and wild-type diabetic mice. The collected results highlight the role of the histamine H₄ receptor in the control of renal reabsorption processes, particularly albumin uptake.