Although
diabetic nephropathy is often a low
renin state, the
renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma
renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal
renin system. PRA and renal vascular responses (
inulin and para-aminohippurate clearance) to graded doses of an
angiotensin II (AngII) antagonist,
irbesartan, were assessed in eight healthy volunteers and 12 patients with
type 2 diabetes mellitus and nephropathy on
a 10 mmol Na intake, to activate the
renin system. Basal PRA was suppressed in
type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to
irbesartan in
type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to
irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to
irbesartan more gradually in the patients with
type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in
type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in
type 2 diabetes mellitus. This increase could account for suppressed circulating
renin, the exaggerated renal
vasodilator response to
irbesartan, and the therapeutic effectiveness of interrupting the
renin system in
diabetic nephropathy.