Evidence against increased glomerular pressure initiating diabetic nephropathy

Bank, Norman; Klose, Ruth M.; Aynedjian, Hagop S.; Nguyen, Dang; Sablay, Leonarda B.

doi:10.1038/ki.1987.83

Cited by 79 publications

(29 citation statements)

References 20 publications

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“…In both studies the SHR rats were hypertensive compared to the WKY rats. In one study [23] no difference was found between SHR and WKY rats with regard to the development of diabetic nephropathy. In the other study [24] the rats were followed for 8 months after the induction of diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…However, in our model, diabetes induced in DS rats resulted in a rapid development of glomerulopathy mostly characterised by mesangial expansion typical of the advanced phase of diabetic nephropathy. The relationship between hypertension and changes in kidney function and morphology in rats with streptozotocin-induced diabetes has previously been evaluated in two studies on spontaneously hypertensive rats (SHR) [23,24]. The SHR rats are considered to be salt-insensitive.…”

Section: Discussionmentioning

confidence: 99%

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Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

et al. 1997

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Summary Diabetic nephropathy tends to develop more readily in patients with a family history of hypertension and/or disturbances in sodium transport across the plasma membrane. This prompted us to study the renal effects of diabetes mellitus in a rat strain which is predisposed to develop salt-sensitive hypertension, the Dahl salt-sensitive rat. Diabetes is associated with several aberrations in the renal handling of sodium, such as elevation of tubular Na + , K + ATPase activity. This effect was more pronounced in Dahl salt-sensitive than in Dahl salt-resistant rats. Severe renal lesions, characteristic of the advanced phase of diabetic nephropathy are very rarely observed in rats with streptozotocin diabetes. However, 2 months after induction of diabetes, the Dahl salt-sensitive rats had morphological signs of advanced glomerular disease. The urinary albumin concentration was very high, but did not correlate with the blood pressure. Non-diabetic Dahl salt-sensitive rats as well as Dahl salt-resistant diabetic and non-diabetic rats had little or no signs of glomerular disease and consistently very low urinary albumin concentrations. [Diabetologia (1997) 40: 367-373]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

et al. 1997

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“…38 - 39 However, micropuncture studies have shown that lowering the blood pressure to normotensive levels in diabetic SHR afforded protection against the development of early diabetic glomerulopathy independently of a reduction in glomerular hydraulic pressure. 40 Angiotensin II has many other actions within the kidney, including effects on mesangial cell contraction and macromolecular uptake through the mesangium, 41 tubular sodium reabsorption, 42 and vasa recta blood flow, 43 all of which might modulate the progression of intrarenal pathology in renal failure. Renal ACE is not influenced by changes in salt balance 22 -44 and is effectively inhibited by ACE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.

1991

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To establish if the benefit of angiotensin converting enzyme inhibitor therapy in retarding progressive diabetic renal injury is due to a specific intrarenal effect or the systemic hypotensive effect, we studied the effect of long-term ramipril treatment on blood pressure, glomerular filtration rate, and urinary protein excretion in streptozotocin-diabetic spontaneously hypertensive rats. The hypotensive effect of ramipril was prevented by a high salt diet, which did not alter the degree of renal angiotensin converting enzyme inhibition. Three weeks after uninephrectomy and induction of diabetes, rats were allocated to three groups. Groups 1 and 2 were given 1% NaCl, whereas group 3 was given water as drinking solution. One week later, groups 2 and 3 received 0.4 mg/kg/day ramipril in their drinking solution, which was continued over a 2-month period. Ramipril produced a blood pressure fall only in water-drinking rats (group 3) despite a similar reduction in plasma and renal angiotensin converting enzyme activity in groups 2 and 3. Salt-loaded rats had a progressive increase in urinary protein excretion over the duration of study. Ramipril treatment prevented an increase in protein excretion only in animals given water and with a reduced systolic blood pressure. Glomerular nitration rate was similar in all three groups. Ramipril treatment improved animal survival independently of a reduction in blood pressure or an effect on proteinuria. Although it is possible that angiotensin converting enzyme inhibitors have specific intrarenal effects reducing progression of diabetic proteinuria, concomitant control of systemic blood pressure appears to be necessary to demonstrate a benefit. (Hypertension 1991;17:497-503) U ncontrolled systemic hypertension is a wellknown cause of progressive renal injury in both humans and experimental animals. 1Hypertension is commonly associated with diabetic renal disease,'-3 and it has been shown to accelerate the rate of development of diabetic nephropathy both in humans 4 and in streptozotocin-diabetic rats. 13 or in other renal disorders. 1415 However, it is difficult to determine from these studies if the beneficial effect of ACE Received February 9, 1990; accepted in revised form November 29, 1990. inhibitors was due to a specific intrarenal effect of ACE inhibition or due to their systemic hypotensive effect.To evaluate this question further, we examined the effect of long-term administration of the ACE inhibitor ramipril on blood pressure, glomerular filtration rate, and proteinuria in streptozotocin diabetic uninephrectomized spontaneously hypertensive rats (SHR). To prevent the hypotensive effect of ACE inhibition, the rats were maintained on a high salt diet, which is known to oppose the blood pressurelowering action of ACE inhibitors. -17 Methods Study Protocol

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“…on the progression of glomerular sclerosis without affecting candidate pathophysiologic mechanisms. Such data were extrapolated into a general scheme of pathophysiology applied to all forms of glomerular sclerosis by taking data as evidence against the importance of such mechanisms in question (40)(41)(42)(43)(44). In this regard, our data showing the unique susceptibility of young remnant glomeruli to sclerosis despite glomerular pressure and size comparable to or even below adult levels point to the significance of host-dependent factors as an important determinant for the progression of glomerular sclerosis, which may potentially be altered by these experimental maneuver^.^ Of note, the notion has been widely accepted in recent years that local or systemic growth factors that promote glomerular hypertrophy may underlie the development and progression of glomerular sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the Unique Susceptibility of Deep Cortical Glomeruli of Maturing Kidneys to Severe Focal Glomerular Sclerosis

et al. 1990

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ABSTRACT. The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in -32-d-old young and >3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli. (Pediatr Res 28: 270-276,1990) Abbreviations BUN, blood urea nitrogen BW, body weight GFR, glomerular filtration rate PAmean, mean planar area of glomeruli Pee, glomerular capillary pressure SBP, systolic blood pressure SNGFR, single nephron glomerular filtration rate sNPX, subtotal nephrectomy In view of the marked functional and structural internephron heterogeneity seen in chronically diseased kidneys in both humans and animals ( 1 -4), various initial immune or nonimmune insults appear to cause loss of a selected population of functioning nephrons. Extensive nephron population loss leads to functional

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Evidence against increased glomerular pressure initiating diabetic nephropathy

Cited by 79 publications

References 20 publications

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.

Mechanism of the Unique Susceptibility of Deep Cortical Glomeruli of Maturing Kidneys to Severe Focal Glomerular Sclerosis

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