Glomerular filtration and tubular reabsorption of albumin in preproteinuric and proteinuric diabetic rats.

Abstract

Microalbuminuria (26-250 mg/d) is considered to be an indicator of incipient diabetic nephropathy in humans in insulin-dependent diabetes (IDD). However, before microalbuminuria is observed, glomerular alterations, such as glycosylation of the glomerular basement membrane and glomerular hyperfiltration, in IDD may result in increased filtration of albumin before any observed increase in albumin excretion. Glomerular and tubular albumin kinetics were examined in streptozotocin (65 mg/kg body wt, i.v.) diabetic, Munich-Wistar rats at 7-10 (untreated) and 50-70 d (poorly controlled with small doses of insulin) after the onset of diabetes and compared with nondiabetic controls. Additional rats in each condition received acute lysine treatment to prevent tubular protein reabsorption. Urinary albumin excretion and nonvascular albumin distribution volumes were measured in the renal cortex and compared with morphometric measurements of interstitial space and the proximal tubule to assess intracellular uptake of albumin in the proximal tubule. Urinary albumin excretion under anesthesia was not different in 7-10-d IDD versus controls (19±3 vs.

Modulation of Incipient Glomerular Lesions in Experimental Diabetic Nephropathy by Hypotensive and Subhypotensive Dosages of an ACE Inhibitor

“…This would indicate that a reduction in systemic blood pressure or in the glomerular filtration rate is not a prerequisite for the antiproteinuric and antirenal growth effect of ACE inhibitors in the early phases of diabetic nephropathy. The discrepancy observed with the subhypotensive dosages of quinapril between reduction of proteinuria and the absence of significant effects on glomerular hyperfiltration is consistent with the notion that the major contributor to increased glomerular filtration of albumin is not hyperfiltration but an increase in macromolecular permeability at the glomerular filtration barrier (5,34). Accordingly, in our study, a positive correlation was found between proteinuria and P alb , whereas proteinuria and the GFR were not correlated.…”

“…The onset of microalbuminuria in diabetes is thought to result from increased glomerular passage of albumin and an eventual decrease in the protein reabsorptive capacity of the tubules (5).…”

Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

“…Thus, it is comparable to nondiabetic wild type in the 10% hypomorphs, but increases from microalbuminuria to macroalbuminuria as Tgfb1 expression increases from 1/2 to ∼3 times normal. Whether the proteinuria in diabetic nephropathy is due to podocyte/glomerular dysfunction and/or to tubule dysfunction is a subject of debate (21)(22)(23)(24). We found that the albuminuria of the 10% hypomorphs was increased 20 fold by switching Tgfb1 expression from low to high in the tubules, but only fourfold by switching in the podocytes.…”

An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats

“…Although our mPBPK model reasonably captures the trends in the modulations in renal clearance, the predictions rely upon changes in renal function, while being limited in identifiability for other factors involved such as proximal tubular reabsorption (F r ) and renal catabolism. Both have been found to be important for albumin (49,50). In these studies, filtered albumin load was elevated 50 to 70 days after induction of diabetes, and it was suggested that the enhanced albuminuria observed was partly glomerular and partly tubular in origin (49).…”