Localization Of The Renal Microvascular Dysregulation In Early Td

Diabetic hyperfiltration is evident not only in humans with T1D, but also in rodent models of T1D. Most experimental studies of renal hemodynamic and glomerular function in diabetes have utilized the streptozotocin (STZ)-treated rat. Renal cross-transplantation studies have established that STZ exerts minimal direct nephrotoxic effects, such that the renal functional changes evident in the STZ rat arise as a consequence of the induction of T1D (1). Within 3 d after STZ injection, renal and glomerular hypertrophy are evident (2), whereas hyperfiltration arises within 1 wk and remains evident for weeks to months (probably dependent on the magnitude of the hyperglycemia). The hyperfiltration can be substantial, as exemplified by our observation of an 80% increase in inulin clearance in Sprague-Dawley rats studied 2 wk after STZ treatment (3). Hence, although there are some limitations in the utility of the STZ rat in studying the processes occurring during advanced DN (2), the STZ rat provides a useful tool for studying the mechanisms underlying diabetic hyperfiltration.

During the 1980s, micropuncture studies in the STZ rat provided the first documentation that diabetic hyperfiltration results from a reduction in preglomerular vascular resistance, with the ultrafiltration coefficient and efferent arteriolar resistance usually unaffected (4,5). This situation increases glomerular plasma flow and capillary hydrostatic pressure, thereby spawning the substantial increase in GFR. The glomerular capillary hypertension in STZ rats is an acutely reversible consequence of insulin deficiency and the resulting hyperglycemia (4). Indeed, acute restoration of euglycemia also restores GFR to normal values in humans with recent onset T1D (6). Hyperfiltration in STZ rats is evident not only at the whole kidney level and in superficial nephrons accessible by standard in vivo micropuncture methods, but also occurs in juxtamedullary nephrons (3). Data obtained through the use of videomicroscopy in concert with the in vitro blood-perfused juxtamedullary nephron technique have confirmed that the increase in GFR can be attributed to a significantly greater afferent arteriolar lumen diameter in STZ kidneys, compared with kidneys from Sham (vehicle-treated) rats, whereas efferent arteriolar diameter is unaffected (3). In addition to the reduced basal arteriolar tone, afferent (but not efferent) arterioles from moderately hyperglycemic STZ rats display attenuated vasoconstrictor responsiveness to norepinephrine (3). Over the course of several studies, we have observed a bell-shaped relationship between blood glucose levels and juxtamedullary afferent arteriolar diameter (Fig. 1). This observation is in accord with previous reports that hyperfiltration occurs in moderately hyperglycemic STZ rats, whereas severe hyperglycemia evokes a reduction in GFR (5).

Fig. 1. Relationship between blood glucose concentration and juxtamedullary afferent arteriolar lumen diameter in kidneys from nondiabetic rats (Sham, o) and rats with STZ-induced T1D (X). The second-order regression line (solid) with 95% confidence intervals (•) is also provided.
Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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