Aims and Methods: This study was carried out to clarify whether the urinary excretion of type IV collagen (u-IV collagen) detected by specific radioimmunoassay, can be used as an indicator for the progression of diabetic nephropathy. Results: u-IV collagen was higher in diabetic subjects with microalbuminuria and overt proteinuria than those with normoalbuminuria, IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, or control normal subjects. u-IV collagen was positively correlated with serum and urinary β₂-microglobulin and negatively with creatinine clearance only in diabetic patients, but not in patients with other glomerular diseases. The serum type IV collagen was not different between all the groups, and not correlated with its urinary excretion. In the advanced diabetic nephropathy, immunoreactive type IV collagen was detected in glomerular basement membrane (GBM), tubular basement membrane and Bowman’s capsule much more than that in the normal kidney. Conclusion: These findings indicated increased production and degeneration of type IV collagen in diabetic nephropathy. It is suggested that augmented turnover of type IV collagen in GBM and tubular basement membrane results in increased concentrations of free u-IV collagen. Therefore, measurement of u-IV collagen may be a useful, specific indicator of the progression of diabetic nephropathy.

We studied the metabolic pathways of dihydroxyphenylalanine (DOPA) and dopamine as well as the cardiovascular and renal responses to a single administration of DOPA (500 mg orally) in stable essential hypertension. We found that after DOPA, stable hypertensive patients compared with controls showed more blood pressure decrease without reflex tachycardia, had lower creatinine clearance but a higher fractional excretion of sodium, and had lower plasma renin activity at the height of DOPA action. Hypertensive patients also showed increased plasma DOPA, the ratio of plasma DOPA to dopamine, and the sum of plasma DOPA and 3-O-methyl-DOPA, as well as increased urinary 3-0-methyl-DOPA and the plasma and urine dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. Finally, despite an augmented post-DOPA glomerular load of DOPA, the predominant source of urinary dopamine, the excretion rates of dopamine and its metabolites remained comparable in hypertensive patients to those in control subjects. These data suggest that, in stable hypertensive patients, exogenous DOPA is to a lesser degree decarboxylated to dopamine, which is more rapidly metabolized intraneuronally. Contrasting with this finding are the hyperdopaminergic features, such as hypernatriuresis with renin suppression and excessive blood pressure decline in the absence of reflex tachycardia. They may be due to an upregulation of renal, vascular, and brain dopaminergic receptors secondary to a preexisting dopaminergic deficiency in stable essential hypertension. {Hypertension 1992;19:634-638) KEY WORDS • DOPA • dopamine • essential hypertension T he possibility that dopamine, an essentially vasodilator and natriuretic catecholamine, may be involved in the pathogenesis of essential hypertension (EH) is still a controversial subject because of the very low plasma free dopamine concentrations and the heterogeneity of the EH syndrome.1 Detection of dopaminergic abnormalities is also made difficult by the fact that dopamine, generated from 3,4-dihydroxyphenylalanine (DOPA) not only in the sympathetic nervous system but also in non-neuronal tissues, is rapidly converted to either 3,4-dihydroxyphenylacetic acid (DOPAC) or 3-methoxytyramine (3-MT) and subsequently to homovanillic acid (HVA respective metabolites, and blood pressure (BP) responses to exogenous DOPA. Moreover, the EH patients were defined only as normal and low renin EH, without respect to other BP characteristics (such as borderline and s-EH), which, in addition to salt sensitivity, 2 proved to be important determinants of the heterogeneity of dopaminergic involvement in EH. 1 We have demonstrated in a previous study 4 that it is possible to detect some hyperdopaminergic patterns in borderline EH patients with measurements of several intermediate steps after an exogenous DOPA-induced increase of circulating DOPA (including metabolites of DOPA, such as 3-O-methyl-DOPA, and of dopamine, such as dopamine sulfate, DOPAC, 3-MT, and HVA in plasma and urine) as well as of renal and vascular...

To explore whether an altered metabolic pathway of dihydroxyphenylalanine (DOPA) may be related to some previously observed dopamine abnormalities in borderline hypertension, we measured basal and DOPA-induced (500 mg orally) changes in blood pressure and pulse rate as well as in three hourly plasma and urine samples. We found that borderline hypertensive patients compared with controls 1) showed a higher baseline urinary excretion of methoxytyramine, a marker of exocytotic dopamine release, with a greater DOPA-induced decrease of systolic blood pressure without reflex tachycardia; 2) had in response to DOPA a blunted plasma DOPA and free dopamine increase but an accentuated plasma dopamine sulfate and urinary DOPAC excretion; and 3) eliminated comparable quantities of dopamine in urine despite a lower rise in the glomerular DOPA load. Furthermore, although DOPA elicited natriuresis in both groups, its effect was greater in borderline hypertensive patients, who lacked the urinary sodium correlation with urinary dopamine excretion seen in control subjects. These data are compatible with increased basal exocytotic dopamine release and accelerated neuronal and renal (extraneuronal) dopamine generation from administered DOPA in borderline hypertension. The DOPA-induced hypernatriuresis exceeding augmented dopamine in borderline hypertensive patients, contrasting with the urinary sodium and dopamine correlation in control subjects, suggests that DOPA induced an additional natriuresis in borderline hypertensive patients by a decrease in renal sympathetic tone because of its central inhibition of sympathetic outflow, which also may account for the absence of reflex tachycardia. {Hyperten-sion 1991;17:997-1002)

Peripheral dopamine (DA) synthesis and release increase during hypertensive stage of spontaneously hypertensive rats (SHR). DA is generated from 3,4-dihydroxyphenylalanine by L-amino acid decarboxylase (AADC). We have studies urinary DA and DA metabolites and the gene expression of neuron and non-neuron specific AADC mRNA in the kidney of SHR. Compared to Wister-Kyoto rats (WKY), there was an increased urinary free DA and DOPAC excretions in 8 and 12 week-old SHR. At the age of 16 weeks, the difference in free DA excretion between SHR and WKY rats disappeared, although the urinary DOPAC excretion remained significantly higher in SHR, but urinary HVA excretion did not differ from WKY rats. The expression of the neuron specific AADC mRNA in the kidney of SHR and WKY rats was not detected, but the non-neuron specific AADC mRNA in the kidney of SHR and WKY rats was detected. The gene expression of the non-neuron specific AADC mRNA tended to decrease with age in SHR. The results suggest that a decrease in renal DA production with age may be caused by diminished expression of non-neuron specific AADC mRNA in kidney.