The kallikrein–kinin system in diabetic nephropathy

Abstract

Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy.

Classical Renin‐Angiotensin System in Kidney Physiology

“…Beyond a role in blood pressure lowering, bradykinin acting via its receptors may also play a role in modifying kidney injury in diabetes. For example, studies in mice lacking bradykinin receptors show that they have dramatic acceleration of albuminuria and glomerular pathology, indicating a protective effect of bradykinin in diabetic nephropathy (164-167, 361). These studies suggest that ACE activity has the potential to modulate renal disease in diabetes via degradation of bradykinin, and that one potential mechanism underlying the benefits of ACE inhibition in diabetic nephropathy (207, 209) might be potentiation of bradykinin effects.…”

Effect of bradykinin on renal mesangial cell proliferation and extracellular matrix secretion

“…Recent studies have found that the KKS could significantly inhibit glomerulosclerosis (Schanstra et al, 2002;Marceau and Regoli, 2004;Kakoki et al, 2004;Tan et al, 2005;Tomita et al, 2012). The kidney contains various components of KKS, and bradykinin (BK), the most important bioactive peptide of KKS, is the final effector exerting the effects described above.…”

Kinin B2receptor does not exert renoprotective effects on mice with glycerol-induced rhabdomyolysis

“…Recent studies [28][29][30][31] show that deletion of B1R and B2R exacerbates the renal phenotype in diabetic mouse models, suggesting that both receptors have a protective effect on diabetic nephropathy by suppressing oxidative stress via NO and prostaglandins. However, because the absence of one of the receptors causes increased expression of the other, it is difficult to determine the precise function of each receptor [28] .…”

“…However, because the absence of one of the receptors causes increased expression of the other, it is difficult to determine the precise function of each receptor [28] . In other models, such as the I/R model [15] the receptors' role was also studied.…”

“…August 6, 2014|Volume 3|Issue 3| WJN|www.wjgnet.com It has been shown that human skeletal muscle can survive for up to 3 or 4 h during circulatory ischemia [28] . In other studies [24] , the authors showed that in the rat glycerol-induced rhabdomyolysis model, the renal mitochondria were already markedly degenerated 3 h after the glycerol application.…”