Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy.

Abstract

Six groups of Munich-Wistar rats underwent micropuncture study 2-10 weeks and morphologic studies 11-13 months after induction of streptozotocin diabetes or after sham treatment. Diabetic rats received diets containing 6% (group D6), 12% (D12), or 50% protein (D50) and were maintained under similar conditions of moderate hyperglycemia by daily injections of ultralente insulin. Age-and weightmatched normal control rats were also given 6% (Group N6), 12% (N12), or 50% protein (N50 (9,10) to result from an augmentation of both glomerular plasma flow rate (QA) and local transcapillary hydraulic pressure difference (AlP). Glomerular morphologic changes resembling those seen in diabetes have been associated with increases in capillary pressures and flows in other experimental forms of renal disease, including ablation ofrenal mass (11-13), high-protein diet (14), and some models of hypertension (15, 16). Furthermore, the extent of glomerular lesions in diabetic rats can be enhanced by maneuvers known to increase glomerular capillary pressures and flows, such as contralateral renal arterial clipping (17), ablation of the contralateral kidney (18), or high-protein feeding (19).Studies to date have not dissociated the effects of glomerular hypertension and hyperperfusion from those of chronic hyperglycemia per se (20)(21)(22). In the present study, glomerular hemodynamic function was deliberately varied in rats with streptozotocin (STZ)-induced diabetes while stable moderate hyperglycemia was maintained by daily exogenous insulin. This approach made it possible to relate the early alterations in glomerular pressures and flows in experimental diabetes to the subsequent development of glomerular injury. METHODSNinety-three adult male Munich-Wistar rats (220-260 g each) were studied. Forty-three rats were made diabetic by a single intravenous injection of STZ (60 mg/kg). Morning blood glucose concentration was determined biweekly. Rats received daily evening injections of ultralente insulin (NOVO Industries, Copenhagen) (23) in doses to maintain blood glucose concentration (BG) between 200 and 400 mg/dl. Diabetic rats were maintained on diets containing 50% (group D50, n = 15), 12% (D12, n = 15), or 6% casein (D6, n = 13). Normal control rats matched for initial body weight received the same diets containing 50% (group N50, n = 18), 12% (N12, n = 16), or 6% casein (N6, n = 16). The composition of the diets was 82% (wt/wt) casein plus carbohydrate, 5% lipid, 1% phosphate, 1% calcium, and 11% other components.Twenty-five diabetic rats and 24 control rats underwent micropuncture study 2-10 weeks (mean 4.2) after STZ injection. Rats were anesthetized with Inactin (100 mg/kg) and prepared for mnicropuncture in standard fashion (24). Euvolemia was maintained by iso-oncotic plasma replacement (25). Inulin (10 g/dl in isotonic saline solution) was also infused at a rate of 1.2 ml/hr. Tubule fluid was collected from superficial proximal tubules for determinations of flow rate and inulin concentration (26). Blood samples fro...

The clinical significance of hyperfiltration in diabetes

“…2). In the 1980s, Zatz showed that haemodynamic rather than metabolic factors mediate diabetic glomerulopathy in the streptozotocin diabetic Munich-Wistar rat [41]. Hyperfiltration was also shown to mediate glomerular injury in the setting of ageing, renal ablation and intrinsic renal disease [42].…”

“…In early diabetes, hyperfiltration at the whole-kidney level may reflect a generalised increase in single-nephron GFR, but a contribution by increased nephron endowment cannot be ruled out. Soon after the onset of diabetic nephropathy, HF mediates glomerular injury [42] Haemodynamic factors predominate in diabetic glomerulopathy [41] Increased proximal tubular resorption of glucose and sodium leads to diabetic HF [43] Blockade of renal tubule growth reduces diabetic HF [44] Fig. 2 Glomerular and tubular theories for the development of hyperfiltration (HF) in diabetes early decreases in whole-kidney GFR may reflect a generalised decrease in single-nephron GFR.…”

“…In animal models of renal damage, including diabetic nephropathy, a decrease in dietary protein intake retards the progression of renal disease [41] while decreasing hyperfiltration at the single-nephron level [6]. Similarly, in patients with type 1 diabetes and GFR <60 ml min −1 1.73 m −2 , a reduction of dietary protein intake from 1.0-1.1 to 0.6-0.7 g/kg daily has been shown to slow the annual rate of decline of GFR from between 6 and 10 min −1 1.73 m −2 to <2 ml min −1 1.73 m −2 [51,52].…”

Effects of candesartan cilexetil on oxidative state and renal function in 5/6 nephrectomized rats

“…Studies in animals with type 1 diabetes mellitus have suggested that ACE inhibitors could reduce glomerular damage by reduction in glomerular capillary pressure. 4, 5 The beneficial influences of ACE inhibitors on renal function may be independent of the effects on systemic blood pressure. 4,5 Findings in experimental models suggest that ACE inhibitors may exert renoprotective effects through haemodynamic as well as non-haemodynamic mechanisms.…”

“…4, 5 The beneficial influences of ACE inhibitors on renal function may be independent of the effects on systemic blood pressure. 4,5 Findings in experimental models suggest that ACE inhibitors may exert renoprotective effects through haemodynamic as well as non-haemodynamic mechanisms. In obese Zuker rats, an animal model with type II diabetes, administration of an ACE inhibitor reduced glomerular injury, while causing little change in glomerular capillary pressure.…”