The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis

Abstract

Aims/hypothesis: We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli. Methods: We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed at 40 weeks. Results: Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19± 0.64 vs 6.45±0.67 g, p<0.001) and had fewer glomeruli (27,402±3,137 vs 34,203±6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=−0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770±541 vs 5,779±1,302 mm 2 , p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group (2.40±0.693 ×10 −3 mm 2 ) than in the LPD control group (1.68±0.374 ×10 −3 mm 2 , p<0.001) and in the NPD diabetic animals (1.71±0.291 ×10 −3 mm 2 , p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals. Conclusions/ interpretation: A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number on the development of renal disease.

Early glomerular alterations in genetically determined low nephron number

“…These results are in line with the finding that in GDNFϩ/Ϫ mice the response to ANG II was comparable to that of the wild-type group (42). But this again is in contrast to low-protein IUGR rats with lower nephron number, in which the expression of ANG II receptor is reduced with additionally altered function because the response to infusion of ANG II is greater and more prolonged in low-protein rats (26). Interestingly, in the follow-up of these rats AT 1 receptor expression already increased before hypertension became manifest (39), thus providing a direct role of the RAS in the development of hypertension in IUGR rats.…”

The Clinical Importance of Nephron Mass

“…128 Chronic Kidney Disease LBW is associated in animals with accelerated progression of Thy-1 nephritis and greater maladaptive responses to induced hyperglycemia and diabetes, consistent with a greater susceptibility to renal injury in the setting of reduced N glom . 63,129,130 Interestingly, in old LBW diabetic rats, podocyte density was reduced and the average area covered by each podocyte was greater compared with NBW diabetic controls. 130 A similar finding of "podocyte insufficiency" was a contributor to rapid progression of diabetic nephropathy among Pima Indians.…”

“…63,129,130 Interestingly, in old LBW diabetic rats, podocyte density was reduced and the average area covered by each podocyte was greater compared with NBW diabetic controls. 130 A similar finding of "podocyte insufficiency" was a contributor to rapid progression of diabetic nephropathy among Pima Indians. 73 This finding was not correlated with N glom in humans but may be a consequence of programmed renal changes in this population.…”

Factors associated with a vicious cycle involving a low nephron number, hypertension and chronic kidney disease

“…95 Similarly, among Pima Indians with type 2 diabetes, a U-shaped association has been demonstrated between birth weight and albumin excretion in both LBW and high-birth weight (HBW; defined as a birth weight over 4500 g) adults. 96 Meanwhile, Jones et al 97 described morphological abnormalities in glomerular podocytes in LBW diabetic animals, which may have a role in the development of proteinuria. 97 These findings likely indicate that intrauterine programming of nephron development may be associated with a decreased nephron number and increased risk of albuminuria.…”

“…96 Meanwhile, Jones et al 97 described morphological abnormalities in glomerular podocytes in LBW diabetic animals, which may have a role in the development of proteinuria. 97 These findings likely indicate that intrauterine programming of nephron development may be associated with a decreased nephron number and increased risk of albuminuria.…”