Mechanisms Of Hyperfiltration In Diabetes

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The pathogenesis of diabetic hyperfiltration is multifactorial. Numerous mechanisms and mediators for this effect have been proposed (Table 1), and are briefly reviewed here. For better clarity, these mechanisms are divided in five areas separately discussed below. However, the reader should be aware of overlap between these processes, and the fact that they act in concert to promote renal hemodynamic alterations in diabetes.

Table 1


1. Factors affecting predominantly afferent arteriolar tone

Hyperglycemia/insulinopenia Advanced glycosylation end products

Atrial natriuretic peptide and extracellular fluid volume expansion

Nitric oxide and blunted tubulo-glomerular feedback

Vasodilator prostaglandins

Increased plasma ketone bodies, organic acids

Increased plasma glucagon levels

Increased plasma levels of growth hormone and insulin-like growth factor-1 Impaired afferent arteriolar voltage-gated calcium channels

Altered responsiveness or receptor density to catecholamines/angiotensin II/TxA2

2. Factors affecting predominantly afferent arteriolar tone

Increased activity of the RAS, endothelin, and vasoconstrictor prostanoids

3. Miscellaneous factors

Protein kinase C

Increased Na+ reabsorption upstream from macula densa Increased kallikrein-kinin activity Abnormalities in calcium metabolism Vascular endothelial growth factor Abnormal myo-inositol metabolism

Tissue hypoxia/abnormalities in local vasoregulatory factors

Metabolic millieu

Considering the simple fact that without the hyperglycemia and other factors characteristic for the diabetic milieu there would be no hemodynamic changes or nephropathy, the diabetic metabolic milieu must contribute. Hyperglycemia and/or insulinopeniaper se [20,33], together with augmented growth hormone and glucagon levels [34,35], have been invoked in this process. Reduction of plasma glucose with initial institution of therapy reduces GFR in both Type 1 and 2 DM [33,36]. In moderately hyperglycemic diabetic rats, normalization of blood glucose levels reverses hyperfiltration [37], and insulin infusion reduces PGC [38]. By contrast, insulin infusion sufficient to produce hyperinsulinemia, with euglycemia, increases PGC and hyperfiltration in normal rats [39]. Further, infusion of blood containing early glycosylation products reproduces glomerular hyperfiltration in normal rats [40]. However, it should be appreciated that the most pronounced changes in renal hemodynamics as compared to nondiabetic animals occur in moderately hyperglycemic rats treated with suboptimal doses of exogenous insulin. Hyperfiltration often does not develop in rats without exogenous insulin treatment, despite moderate hyperglycemia. This finding suggests that some insulin levels, in concert with hyperglycemia, are necessary for development of renal hemodynamic changes in diabetes. Whether these effects are linked to vasodilator actions of insulin remains to be established.

There is growing evidence suggesting separate physiological and pathophysiological effects of C-peptide [41], a part of the endogenous insulin molecule that is not contained in exogenous insulin preparations. In addition to alterations in plasma insulin levels and actions, it has been suggested that the lack of C-peptide in diabetic rats also contributes to hyperfiltration [42,43].

Vasoactive factors

Apart from the above-mentioned mechanisms which are closely related to the diabetic metabolic milieu, there is a substantial evidence suggesting that renal hemodynamic alterations are a consequence of imbalance between the vasoactive humoral systems controlling the glomerular circulation. It is assumed that the balance between factors influencing the afferent arteriolar tone is shifted towards vasodilators, whereas opposite could be expected on the efferent arteriole.

Atrial natriuretic peptide (ANP), which induces afferent dilation and efferent constriction, represents one such promising candidate for mediating diabetic hyperfiltration. Plasma ANP levels are elevated in diabetes [44], and blockade of the ANP action with an antibody [44] or a specific receptor antagonist [45] blunts hyperfiltration in diabetic rats. It is likely that altered levels of ANP in diabetes are a consequence of an increase in total exchangeable body sodium and the hypervolemic state [46,47], although resistance to ANP may be also involved [48]. In any case, these observations suggest that sodium homeostasis is an important factor in the pathogenesis of hyperfiltration.

Nitric oxide (NO) is a potent vasodilator acting on both afferent and efferent arterioles, presumably with predominant afferent actions in vivo [49]. In mammalian tissues, NO is synthesized by a family of isoenzymes known as nitric oxide synthases (NOS). Considering its renal actions, NO is a good candidate for mediating diabetic hyperfiltration. Paradoxically, diabetes is considered to be a state with reduced NO bioavailability [50,51]. However, as recently reviewed [52], the situation in the diabetic kidney, in particular at the early stages of diabetes, is more complex.

Most of the renal hemodynamic studies conducted in hyperfiltering rats demonstrated increased renal hemodynamic responses and near-normalization of renal hemodynamics in response to inhibition of NO synthesis with nonspecific NOS inhibitors (i.e., affecting all NOS isoforms) [53-55]. More recent studies attempted to identify the contribution of individual NOS isoforms in the process. We have recently focused on renal hemodynamic roles of neuronal NOS (nNOS, NOS1). This isoform is particularly of interest in the diabetic kidney. Under physiological conditions, NOS 1-derived NO counteracts afferent vasoconstrictor signals mediated by the tubuloglomerular feedback mechanism, thus contributing to the control of PGC [56]. The renal vascular tree is more sensitive to the systemic NOS1 inhibition in diabetic rats, as compared to controls [57]. Furthermore, we observed complete amelioration of hyperfiltration in response to intrarenal selective NOS1 inhibition in conjunction with increased number of nNOS-positive cells in MD regions of diabetic kidneys [58]. These observations identified NOS1-derived NO as an important player in the pathogenesis of diabetic hyperfiltration, and are in accordance with previous reports showing blunting of the tubuloglomerular feedback in diabetic rats [59,60], as further discussed below. There is also evidence suggesting that activity of the endothelial NOS isoform (eNOS, NOS3) may be increased, and responsible for renal NO hyperproduction in diabetes [61,62].

In addition to possible direct effects of diabetes on NOS activities, the NO-mediated alterations in renal hemodynamics may be related to increased activity of factors, which act as NO-dependent vasodilators or activate NO-cGMP pathway as a part of their signal transduction. De Vriese, et al [63] reported that neutralization of vascular endothelial growth factor (VEGF) with an antibody ameliorated diabetic hyperfiltration. VEGF has been implicated with non-hemodynamic pathways in the pathogenesis of diabetic complications, and also possesses vasomotor effects mediated by NO. Some other factors implicated in the pathophysiology of diabetic glomerulosclerosis, such as TGF-beta and leptin, also signal in part via NO. However, whether these pathways may have impact on glomerular hemodynamics remains to be elucidated.

Enhanced production of reative oxygen species (ROS) appears to be an important mechanism in the pathophysiology of diabetic complications, including nephropathy. Their role has been validated in long-term studies [64,65]. ROS are involved in diabetes-induced alterations in lipids and proteins, cellular signaling [66], inactivation of NO [67], and hemodynamics, acting predominantly as vasoconstrictors [68].

Hemodynamically oriented studies have suggested that ROS, as renal vasoconstrictors, decrease bioavailability of NO or limit the buffering capacity of NO against vasoconstrictors [69-71]. Therefore, one would expect that the net effect of this imbalance would result in renal vasoconstriction. However, this is difficult to reconcile with the fact of diabetic hyperfiltration. Importantly, there is no evidence demonstrating the effect of ROS scavenging on basal arteriolar tone in diabetic rats [70]. Considering the NO-ROS interaction, one would expect enhanced afferent vasodilator responses to antioxidants in diabetes.

In contrast, in vivo studies demonstrated that antioxidant treatment may normalize hyperfiltration in diabetes [64]. Considering the decrease in filtration fraction (FF) in diabetic rats treated with antioxidants, which was observed, one would expect efferent arteriolar effects of antioxidant treatment. These data suggest that these renal microvascular effects are attributable not only to protection of NO from quenching, but also to other mechanisms. One of those mechanisms compatible with the long-term glomerular hemodynamic actions of antioxidants could be, for example, inhibition of angiotensin II (Ang II) signaling via ROS [66].

A role for cyclooxygenase (COX) metabolites of arachidonic acid in the pathogenesis of diabetic nephropathy has been suggested in a number of clinical and experimental studies. Schambelan, et al [72] demonstrated an increase in conversion of exogenous arachidonate to prostaglandin E2 (PGE2), prostaglandin F2alpha, prostaglandin D2, and thromboxane B2 (TxB2) in glomeruli from diabetic rats. In the early stages of nephropathy, vasodilatory prostaglandins, such as prostaglandin E2 and prostacyclin, have been implicated in mediating alterations in renal hemodynamics in humans with Type 1 DM [73-76], as well as in experimental models of diabetes [77-80]. As demonstrated by Jensen, et al [77], inhibition of PG synthesis results in significant reductions in SNGFR, QA and PGC.

The above mentioned evidence about the role of PG in the renal hemodynamics in diabetes relied on measurements of renal function in response to nonspecific inhibitors that inhibit both COX isoenzymes. More recent studies focused on contribution of individual isoforms in the development of renal hemodynamic changes in diabetes. These studies demonstrated increased expression of COX-2 isoform in the diabetic kidney, and a modest effect of the selective COX-2 inhibition on glomerular filtration rate in diabetic rats as compared to COX-1 expression and acute inhibition [81].

Diabetes-related abnormalities of other vasodilator mechanisms have also been suggested, with findings of activation of the kallikrein-kinin system [82-84]. However, studies with kinin receptor antagonists have thus far proven inconsistent [85-87]. Earlier studies suggested that diabetic hyperfiltration might be at least in part attributable to increases in growth hormone [35] and potentially insulin-like growth factor levels. Current evidence suggests that although active in the pathophysiology of glomerular hypertrophy, growth hormone contribution to renal injury in diabetes has a minor hemodynamic component [88].

With respect to the delicate balance between dilators and constrictors in the control of glomerular hemodynamics, reduced afferent or mesangial actions of vasoconstrictor systems may also contribute. These mechanisms include reduced glomerular receptor sites for the vasoconstrictors Ang II and thromboxane [89,90]; and altered vascular responsiveness to catecholamines and Ang II [91-93].

The role of vasoconstrictor systems is, however, more complex. In apparent contrast to the reduced preglomerular and glomerular actions of some of these systems, inhibition of vasoconstrictor systems such as the RAS [26], endothelin (ET) [94], or thromboxane A2 [95,96] has beneficial effects on the development of nephropathy including amelioration of diabetic hyperfiltration. The most plausible explanation for this phenomenon is that the reduction of hyperfiltration by inhibition of these substances is achieved, at least in part, by inhibition of their efferent arteriolar actions. This also suggests that, unlike the preglomerular vasculature, diabetes is associated with normal or increased efferent actions of vasoconstrictors. Supporting this view are our whole kidney data showing an increase in renal hemodynamic vasodilator response to Ang II [92] in conjunction with reduced FF in diabetic rats. In parallel, Hollenberg's group have repeatedly documented enhanced activity of the renal RAS in both types of diabetes by demonstrating enhanced hemodynamic responses in these patients as compared to non-diabetic subjects [97,98]. It should be noted that similar to the glomerular microcirculatory pattern in general, renal hemodynamic responses to various mediators in experimental diabetes are largely dependent upon the state of metabolic control and insulin treatment. These differences may explain some disparate findings of studies exploring the activities of vasoactive systems in diabetes.

Alterations in signal transduction

There is convincing evidence suggesting the role of activation of the protein kinase C (PKC) enzyme family in the pathogenesis of diabetic complications. Importantly, some of these iso-enzymes are not only activated by hyperglycemia via de-novo synthesis of diacylglycerol, but also operate in signaling cascades of some vasoactive peptides, such as Ang II. Amelioration of hyperfiltration, associated with an overall renoprotective effect in the diabetic kidney, was observed in studies with newly available inhibitors of PKC [99].

In addition to PKC, other signaling pathways that are involved in the control of vascular tone are also activated in renal cells in some models of diabetes. For example, the p38 module of mitogen-activated protein kinases and Akt/PKB fulfill those criteria [100-105]. The renal hemodynamic impact of increased activities of such pathways represents a promising direction for future research.

Renal sodium handling and tubuloglomerular feedback. In the normal kidney, cells of the macula densa (MD) sense early distal intratubular concentrations of Na+ and Cl- and in response to increasing ion concentrations, they send vasoconstrictor signals to the afferent arterioles. This autoregulatory mechanism, known as tubuloglomerular feedback (TGF), prevents excessive NaCl losses from the organism. Earlier studies suggested blunting of the TGF in experimental diabetes, resulting in a reduction of afferent constrictor signals [59,60].

More recently Vallon, et al [106,107] demonstrated that reduced TGF activity may be simply a result of increased Na+ tubular reabsorption via Na+/glucose cotransport, leading to reduced electrolyte delivery to the distal nephron. The same group extended this concept by linking the increases in proximal tubular reabsorption in diabetes to tubular hypertrophy induced by enhanced activity of ornithine decarboxyase (0DC)[108]. The concept is further supported by clinical and experimental observations demonstrating paradoxical increase in

GFR in response to a low salt diet [109,110]. However, this complex of observations suggesting the role of distal sodium delivery into the MD region is in contradiction to findings by other groups. Long-term studies showed that amelioration of hyperfiltration with some degree of nephroprotection in diabetic rats can be achieved by sodium restriction [111,112]. It is possible that mechanisms described by Vallon and co-workers represent short-term adjustments of renal hemodynamics in diabetes, whereas long-term treatment with a low salt diet can ultimately reduce hyperfiltration and be beneficial via a wide spectrum of mechanisms.

Intrinsic defects in glomerular arterioles, electromechanical coupling

Using videomicroscpy in isolated blood-perfused juxtamedullary nephrons, Carmines and co-workers [113,114] described several diabetes-induced alterations in afferent arteriolar ion channels that can result in increased baseline diameter and impaired responses to vasoconstrictors. Diabetic rats have suppressed vasoconstrictor-induced increases in intracellular Ca2+ concentrations due to functional defects in afferent arteriolar L-type calcium channels [113]. Subsequent studies [114] implicated increased expression and function of the ATP-sensitive K(+) channels (K-ATPc) in the renal afferent arteriolar dilation which occurs in experimental diabetes.

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