Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Abstract

The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

Plasma potassium, diuretic use and risk of developing chronic kidney disease in a predominantly White population

“…However, we do not have data on urinary ammonia excretion, so we could not further investigate this mechanism. Another mechanism proposed includes the renoprotective effects of higher plasma potassium by upregulating renal kinins, such as kallikrein [52]. Experimental studies showed that an increase in plasma potassium concentration reduces cultured vascular smooth muscle cell proliferation [53], inhibits free radical formation from endothelial cells and macrophages [54], and inhibits platelet aggregation and arterial thrombosis [55,56].…”

Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients

“…In an albumin-overload rat model of tubulointerstitial damage, Ardiles et al (29) showed that high potassium intake increased renal kallikrein expression and decreased blood pressure, profibrotic tissue growth factor b, and tubulointerstitial fibrosis. Data on plasma kallikrein were not available in our RTR cohort, so we could not investigate this possible mechanism.…”

Conditional knockout of collecting duct bradykinin B2receptors exacerbates angiotensin II-induced hypertension during high salt intake

“…3,6,8 Furthermore, the B 2 R forms a complex with angiotensin converting enzyme, and this is thought to play a role in cross-talk between the renin-angiotensin system (RAS) and KKS. 3,6,9 The integrative role of KKS is further supported by involvement of B 2 R activation in renin and NO release. 6,10-12 These interactions may significantly contribute to the regulation of kidney function.…”

“…Indeed, several studies have suggested that inappropriate function of KKS can contribute in hypertension. 2-4,9-11 It is likely that the KKS selectively buffers the activity of vasoconstrictors such as angiotensin II (ANG II).…”

“…In order to delineate the integrative role of KKS, particularly B 2 R - RAS interactions on the development of salt and ANGII-dependent forms of hypertension and potentially in progression of a variety of kidney diseases, 2-6,9 we utilized a gene targeting strategy to inactivate B 2 R specifically in the collecting duct. We hypothesized that Bdkrb2 gene inactivation in the collecting duct favors enhanced tubular sodium retention during high salt intakes and causes salt-sensitive hypertension and hypertension-associated end-organ damage.…”