Abstract
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.
Highlights
Genetic knockout models are fundamental to understand the role of this specific histamine receptor subtype in kidney function and differentiate between off-target and on-target histamine H4 receptor effects
As megalin expression is inversely correlated with that of NHE3 [25], we evaluated the expression of this tubular exchanger
Diabetic wild-type mice but not H4 R−/− showed an increase in AQP7 (Figure 9b) without significant differences in the glycosylation ratio compared to the relative controls (Figure 9c)
Summary
Genetic knockout models are fundamental to understand the role of this specific histamine receptor subtype in kidney function and differentiate between off-target and on-target histamine H4 receptor effects. Histamine H4 receptor knockout (H4 R−/− ) mice were generated soon after the histamine H4 receptor discovery [9] and initially used to demonstrate the role of the histamine. Histamine was suggested to be involved in the etiopathology of diabetes complications [17], nephropathy in particular [18], no study to date involved diabetic H4 R−/− mice and evaluated their susceptibility to developing diabetic nephropathy. The present study aims to clarify the functional role of renal histamine H4 receptor and its involvement in renal pathophysiology through the phenotypic characterization of healthy or diabetic
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