Regulation of renal kallikrein synthesis and activation by glucocorticoids

Abstract

The effects of endogenous and exogenous glucocorticoids on renal active and prokallikrein levels (ng/mg protein) and in vivo kallikrein synthesis rate were studied in the conscious rat. Within two hours after low dose methylprednisolone (MP, 0.0125 to 0.05 mg/100 g body wt), active kallikrein and prokallikrein fell (29.1 +/- 2.3 and 35.1 +/- 2.7 ng/mg protein, respectively, compared to 38.4 +/- 3.7 and 42.7 +/- 3.4 in vehicle-treated rats, P less than 0.05 or less). These changes were accompanied by a significant fall in prokallikrein synthesis rate relative to total protein synthesis. The reductions in active and prokallikrein levels were transient, dissipating by six hours. With increasing MP doses, there was further dose-dependent reduction in active kallikrein. However, prokallikrein levels increased to normal as the MP dose was increased despite continued suppression of synthesis, suggesting that prokallikrein activation was inhibited. Renal kallikrein levels were also examined in relation to changes in endogenous glucocorticoid levels. In intact rats, three hours after plasma corticosterone peaked (10 p.m.), active and prokallikrein levels were 30.2 +/- 2.9 and 27.0 +/- 1.6 ng/mg protein, respectively, compared to 36.9 +/- 2.3 and 37.2 +/- 2.6 (P less than 0.005) three hours after the corticosterone nadir (11 a.m.). Furthermore, adrenalectomy increased active and prokallikrein (47.3 +/- 4.8 and 87.3 +/- 6.0 ng/mg protein, respectively), compared to levels in intact or shamoperated rats (intact: 32.9 +/- 2.9 and 54.9 +/- 5.3 ng/mg protein, P less than 0.01 or less). Adrenalectomy also eliminated the diurnal changes in kallikrein levels seen in intact rats. These data suggest that renal prokallikrein synthesis and activation are physiologically regulated by glucocorticoids.

Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus

“…For example, a low physiological dose of the glucocorticoid methylprednisolone reduces in vivo protein synthesis of rat renal KLK1 within 2 h (419). Renal KLK1 levels in the rat are also inversely proportional to diurnal changes in corticosterone concentrations (419). In addition, dexamethasone decreases KLK1 mRNA and protein levels in AR42J rat pancreatic cancer cells within 12 h of treatment (420).…”

Ontogeny of the intrarenal kallikrein-kinin system: Proposed role in renal development

“…Expression of the renal kallikrein gene is suppressed in obstructive nephropathy and in the chronic phase of renovascular hypertension (El-Dahr et al, 1993a,b;Von Thun et al, 1994). Corticosteroids downregulate pancreatic kallikrein gene expression (Rosewicz et al, 1991) and renal kallikrein synthesis (Jaffa et al, 1990).…”