Osamu Nakashima

Role of Urinary Arginine Vasopressin in the Sodium Excretion in Patients With Chronic Renal Failure

Patients with chronic renal failure show almost equal levels of sodium excreted in the urine as healthy subjects through an increase of the fractional excretion sodium (FE(Na)). The mechanisms of this adaptation, however, are unknown. Recently, urinary arginine vasopressin (AVP) has been shown to inhibit the antidiuretic action of plasma AVP in the collecting ducts of rabbits and rats. In this article, the roles of plasma and urinary AVP are examined with other hormones in the sodium excretion of 57 patients with chronic renal disease. The fractional excretion of AVP, plasma atrial natriuretic peptide (ANP) and endothelin-1 (ET-1), urinary ET-1, and FE(ET-1) correlated with the decrease of creatinine clearance (Ccr). Multiple and stepwise regression analyses showed that FE(AVP) is the major dependent determinant for FE(Na) (adjusted r2 = 0.78). These results suggest that the increase of AVP excretion per remaining nephron could be a cause of the increase of FE(Na) in patients with renal failure. Although plasma AVP works as an antidiuretic hormone, urinary AVP serves as an intrinsic diuretic, especially in patients with chronic renal failure.

Mitogen-activated protein kinase cascade and cell cycle-related genes in the kidney

Recent studies have shown that mitogen-activated protein kinase (MAPK) consists of at least 3 subfamilies, including the classical MAPK, stress-activated protein kinase/c-Jun N-terminal kinase, and p38 kinase. Transforming growth factor (TGF)-β-activating kinase-1 (TAK1) is a novel MAP kinase kinase (MAPKK) that is reported to stimulate the p38 kinase and/or c-Jun N-terminal kinase pathway. TAKdN, the active form of TAK1, inhibits [3H]-thymidine uptake, and reduces the percentages of cells in the S and G2/M phases of the cell cycle. TAKK63W, the negative, or inactive form of TAK1, ameliorates the inhibition of3H-thymidine uptake and the percentages of cells in S and G2/M phases induced by TGF-β. Overexpression of TAKdN inhibits cyclin D1 gene promoter activity and protein expression. In contrast, constitutive active MKK1, the classical p42/44 MAPK activator, increases cyclin D1 promoter activity and protein level. Overexpression of the active form of MKK1 increases [3H]-thymidine uptake, while the inactive form decreases the uptake. To elucidate the mechanisms of the cell cycle of mesangial cells, we produced adenovirus vectors containing the coding sequences of cyclin D1 (AxCAD1), p16INK4 (AxCAp16), and p21CIP1 (AxCAp21), and investigated whether transfer of these genes changes platelet-derived growth factor-and endothelin-1-induced proliferation of rat mesangial cells. AxCAp16 and AxCAp21 inhibits [3H]-thymidine incorporation and the mitogen-induced increase in cyclin-dependent kinase-4 activity, and reduces the percentage of cells in the S phase as well. Overexpression of cyclin D1 increases the percentage of the cells in the S and G2 phases, and reduces cell size. These findings suggest that p16INK4 and p21CIP1 function as inhibitors of the proliferation of mesangial cells, induced by growth-promoting factors, and that deregulated expression of cyclin D1 causes disturbances in the cell cycle.