The role of urinary kininogen in the regulation of kinin generation

Abstract

The kallikrein-kininogen-kinin system has been postulated to play a role in the regulation of blood pressure and modulation of renal salt and water transport. The activity of this system has usually been determined by measurements of urinary kallikrein excretion. However, urinary kallikrein rarely correlates with simultaneously measured urinary kinins. To further evaluate the factors influencing urinary kinin excretion, we evaluated the role of urinary kininogen in this system. Urines were analyzed from normal subjects and individuals with untreated essential hypertension and end-stage renal disease. Intact urinary kininogen was significantly correlated with urinary kinins in normal subjects (r = 0.65, P = 0.003) and essential hypertensives (r = 0.52, P = 0.026). In both essential hypertension and end-stage renal disease, urinary kinins were significantly decreased (8.00 +/- 1.93, 0.90 +/- 0.18, P less than 0.05, respectively) compared to controls (23.73 +/- 5.20). In essential hypertensives, the reduction in urinary kinins was paralleled by a reduction in intact kininogen with a normal excretion of kallikrein. In end-stage renal disease, the reduction in kinins was paralleled by a reduction in kallikrein with a normal excretion of intact kininogen. This data suggests that kininogen may be an important determinant of urinary kinin excretion in various disease states.

Increase in Renal and Urinary Low and High Molecular Weight Kininogens during Chromate-Induced Acute Renal Failure in the Rat: Evidence for Renal Kininogen Production

“…Changes in urinary kininogen simi lar to those of renal kallikrein have been described in response to both high or low sodium intake suggesting that urinary kininogen, like renal kallikrein, is linked to the regulation of sodium balance [20], The same authors re ported that urinary kininogen excretion was reduced in essential hypertensive humans but remained unchanged in end-stage renal disease [19], However, because tissue kini-nogen was not measured in these previous studies, no further evidence for renal production other than changes in urinary excretion could be demonstrated. In the present report, by measuring kininogen in the plasma, renal tissue and urine, it is shown that intrarenal production can be enhanced in response to nephrotoxic substances.…”

“…Whereas a large number of investigations have fo cused on renal production and excretion of kallikrein, the kininogen levels have not been extensively studied during the development of kidney dysfunction. However, the avai lability of kininogen, as kallikrein substrate, is an important limiting factor to be considered before suggesting any role for renal KKS [19,20], In rats, 3 forms of kininogens have been identified: one of high molecular weight (HMW, 110,000 D)and one of low molecular weight (LMW, 66,000 D). Both forms are kinincontaining proteins and can be hydrolyzed by plasma and tissue kallikreins to release kinin, a potent natriuretic, diuretic and vasodilating peptide [1,2], The third type of kininogen, named T-kininogen, because it releases T-kinin (Ile-Ser-bradykinin) only in the presence of high concentra tions of trypsin, has been identified in the rat only [21], Because T-kininogen is resistant to kallikrein hydrolysis, the release of T-kinin under physiological conditions is controversial, although a T-kininogenase has been identi fied in the rat submandibular gland [22], However, T-kininogen is considered as a major protein of the acute phase of inflammation [23].…”

Bradykinin System and Type 2 Diabetes

“…On the other hand, we observed reduced levels of total urinary kininogen in type 2 diabetic patients.This observation might be a reflection on the utilization of kininogen to form BK, a proinflammatory agent as previously reported [19,20]. BK1R and BK2R antagonists may normalize the diabetic state in experimentally induced diabetes in mice [21].…”

Intrarenal Kallikrein-Kinin Activity in Acute Renovascular Hypertension in Dogs

“…The availability and level of urinary kininogen may be an important determinant of urinary kinin excretion in a disease state [34], The substrate from which urinary kinin is derived is a low-molecular-weight kininogen, which is synthesized by the liver and appears in the urine as result of glomerular filtration [35], or from the secretion of kininogen syn thesized by the kidney [36], Interaction of renal kallikrein with kininogen within the kidney results in generation of lysyl-bradykinin. an event regulated not only by the availability of the substrate (kininogen) and the enzyme (kallikrein) but by other factors, such as changs in urinary pH [37], presence of kallikrein inhibitors [38] and various kininases [39], and ionic concentration [40], Therefore, the final interrenal concentration of kinin should be the result of a balance between their formation and destruction.…”