Histamine and diabetic nephropathy: An up-to-date overview

The classification of diabetic nephropathy (DN) as a vascular complication of diabetes makes the possible involvement of histamine, an endogenous amine that is well known for its vasoactive properties, an interesting topic for study. The aim of the present review is to provide an extensive overview of the possible involvement of histamine in the onset and progression of DN. The evidence collected on the role of histamine in kidney function together with its well-known pleiotropic action suggest that this amine may act simultaneously on glomerular hyperfiltration, tubular inflammation, fibrosis development and tubular hypertrophy. Diabetic nephropathy (DN) affects approximately one-third of diabetes mellitus patients and is associated with a substantially elevated mortality rate [1], which is due to an increase in all-cause mortality and a concomitant decline in renal function. The main pharmacological strategies for its treatment currently involve the blockade of the renin–angiotensin–aldosterone (RAAS) system. However, these approaches are suboptimal and their efficacy greatly depends on the early initiation of therapy. The search for new therapeutic strategies is therefore highly warranted, but still a challenge that requires a better understanding of DN pathogenesis. DN can be considered the result of the interactions between multiple metabolic and haemodynamic factors that activate common intracellular signalling pathways, such as protein kinase C (PKC), mitogen activated protein kinase (MAPK), and nuclear factor-κB (NF-κB), which, in turn, trigger the production of cytokines and growth factors, leading to renal disease [2]. The RAAS system, endothelin and urotensin II are vasoactive hormones that have been extensively studied. Other mediators may be involved, although their relation to DN is still speculative. In particular, histamine, in keeping with its well-known vascular and pro-inflammatory effects, is an interesting target for exploration. Indeed, DN is considered a microvascular compliance of diabetes which establishes a vicious circle between glomerular hyperfiltration, tubular inflammation, hypertrophy and interstitial fibrosis development, with synergistic effects. The identification of mediators that can simultaneously affect these multiple events would translate into new pharmacological targets. Histamine was initially related to the vascular genesis of glomerular hyperfiltration. However, a more complex role for histamine can be hypothesised since the tubular hypothesis of DN pathogenesis was postulated. This review aims to elucidate histamine’s contribution to the vicious circle of DN.