The Interplay between Histamine H(4) Receptor and the Kidney Function: The Lesson from H(4) Receptor Knockout Mice

Previous studies implicated the histamine H(4) receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H(4) receptor knockout mice (H(4)R(−/−)). Healthy and diabetic H(4)R(−/−) mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H(4)R(−/−) and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H(4)R(−/−) mice displayed a higher basal glycemia. H(4)R(−/−) mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H(4)R(−/−) 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 H(4)R(−/−) 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 H(4)R(−/−) mice. The AQP1 and AQP7 patterns were also different between H(4)R(−/−) and wild-type diabetic mice. The collected results highlight the role of the histamine H(4) receptor in the control of renal reabsorption processes, particularly albumin uptake.