Atrial natriuretic peptide(31-67) inhibits Na+ transport in rabbit inner medullary collecting duct cells. Role of prostaglandin E2.

Atrial natriuretic peptide (ANP)(31-67), a portion of the atrial peptide prohormone, circulates in humans, and its plasma level varies with atrial pressure. Like the more widely studied carboxy-terminal fragment ANP(99-126), ANP(31-67) stimulates natriuresis and diuresis. We examined the mechanism of this natriuresis by measuring the effects of ANP(31-67) on Na+ transport in cells of the rabbit inner medullary collecting duct (IMCD). ANP(31-67) (10(-8) M) caused a 26 +/- 4% inhibition of oxygen consumption (QO2); half-maximal inhibition occurred at 10(-11) M, suggesting a physiologic effect. This effect was not additive with either ouabain or amiloride, suggesting that it reflected inhibition of Na+ transport-dependent QO2. ANP(31-67) reduced the amphotericin-induced stimulation of QO2 consistent with inhibition by this peptide of the Na(+)-K(+)-ATPase. In addition, ANP(31-67) reduced ouabain-sensitive 86Rb+ uptake under Vmax conditions. Several lines of evidence indicated that PGE2, a known endogenous IMCD Na(+)-K(+)-ATPase inhibitor, mediates pump inhibition by ANP(31-67). Thus, ANP(31-67) inhibits Na+ transport by inhibiting the Na(+)-K(+)-ATPase of IMCD cells, an effect mediated by the generation of PGE2.

Natriuretic peptides and the kidney: current concepts.

The field of study of natriuretic peptides becomes more complex as we enter the second decade since their discovery. The attractive hypothesis that a single peptide secreted by the atria could regulate the physiological responses to salt and water loading has proven simplistic. Rather the atrial natriuretic peptide story has opened the door on a whole family of peptides, secreted from the atria, the ventricles, the brain, and even the kidney itself, all working in concert to achieve this regulation. The regulation of renal function by natriuretic peptides is presumably the result of the integration of these different peptides effects. Thus while atrial derived NP circulates and has direct effects on the glomerulus, other sources of NP (such as the kidney) may be responsible for some of the tubular effects of NP. Further definition of the mechanisms of regulation of the kidney derived NP are needed before any further conclusions can be drawn.

Characterization of ANP receptors in rabbit inner medullary collecting duct cells.

The final urinary Na+ concentration is determined in the inner medullary collecting duct (IMCD) and is under hormonal control. In suspensions of IMCD cells we have previously shown that atrial natriuretic peptide (ANP) inhibits Na+ transport-dependent O2 consumption and causes an increase in cellular guanosine 3',5'-cyclic monophosphate (cGMP) content. In this study we sought to identify and characterize the receptor for ANP in these cells. Equilibrium binding studies revealed a single class of cell surface ANP receptors of high affinity (Kd = 66.2 pM) with a total number of 3,000 sites/cell. Specificity of these receptors was shown by the rank order of binding affinities for ANP analogues: ANP-(1-28) = ANP-(4-28) greater than ANP-(5-28) much greater than ANP-(5-25). We have further defined this receptor in a solubilized cell preparation and found it to be of molecular mass 130 kDa by affinity cross linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. This is the first characterization of an epithelial cell receptor for ANP; as in other systems this receptor appears to be linked to transport processes via the production of cGMP.

Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy.

BACKGROUND: The clinical manifestations of fibrillary-immunotactoid glomerulopathy are still being appreciated. It is unclear whether fibrillary-immunotactoid glomerulopathy actually represents two distinct clinicopathological entities, fibrillary glomerulopathy (FG) and immunotactoid glomerulopathy (ITG), or a single disease with different ultrastructural variants. METHODS: To address these issues, we analysed the clinical features of 186 patients with fibrillary-immunotactoid glomerulopathy referred to our institutions (25 patients) or reported in the literature (161 patients). In separate analyses, patients were subclassified as having either fibrillary glomerulopathy (FG) or immunotactoid glomerulopathy (ITG) according to fibril diameter (FG<=30nm, ITG>30 nm) or arrangement (FG, random; ITG, focally organized). RESULTS: Proteinuria (FG approximately 100%, ITG approximately 100%), nephrotic syndrome (FG approximately 71%, ITG approximately 82%), haematuria (FG approximately 71%, ITG approximately 64%), hypertension (FG approximately 67%, ITG approximately 45%), and renal insufficiency (FG approximately 54%, ITG approximately 42%) were frequent clinical correlates of both FG and ITG, irrespective of the ultrastructural criteria for diagnosis. Twenty-five patients presenting to our institutions (24 FG, 1 ITG) were divided into three groups based on rate of decline of GFR (mean slope of 1/serum creatinine versus time: group 1 -0. 103+/-0.238; group 2 0.121+/-0.040; group 3 0.466+/-0.318) in an attempt to identify clinical predictors of progression at presentation. Rapid progressors (Group 3) had an increased incidence of nephrotic syndrome and tended to have higher blood pressure than patients with milder disease, but did not differ from other groups in age, prevalence of haematuria or degree of renal insufficiency. The number of patients requiring dialysis was 0/10 in group 1, 2/6 in group 2, and 2/4 in group 3 over a follw-up period 47+/-46, 55+/-32, and 19+/-19 months respectively; two predialysis deaths being recorded in group 3. Four patients received five renal allografts (one patient being transplanted twice) and were followed for 4-11 years. Whereas recurrence of FG was documented in three allografts undergoing post-transplant biopsy, the rate of deterioration of GFR was invariably slower in allografts than native kidneys (mean slope of 1/Cr versus time: 0.036+/-0.01 versus 0. 0301+/-0.18 respectively). The strength of association between FG-ITG and lymphoproliferative malignancy varied depending on whether patients with monoclonal-gammopathy-associated fibrillary deposits were included or excluded from the analysis. CONCLUSIONS: We contend that patients presenting with Congo-red-negative fibrillary deposits on renal biopsy should be evaluated carefully for monoclonal-gammopathy and cryoglobulins, but there is insufficient published data, as yet, to justify subclassification of FG and ITG as distinct clinical entities. Indeed, we argue that it remains to be determined if FG-ITG represents a unique condition or a forme fruste of cryoglobulin- or gammopathy-associated renal disease. Although the optimal treatment for FG-ITG has not been determined, renal transplantation appears an attractive option in patients with end-stage renal failure.