February 2009
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Prevention and Treatment of Diabetic Nephropathy: New Approaches
Current therapies to correct classic factors appear insufficient to fully prevent renal complications.
By Toshio Miyata, MD, PhD; and Charles van Ypersele de Strihou, MD
The incidence of diabetic nephropathy remains worrisome despite major therapeutic advances. Classical factors contributing to its pathology (eg, hypertension, obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia) are now amenable to treatment. More recently, the experimental study of animals has incriminated newer culprits such as hypoxia, oxidative stress, and advanced glycation, raising several questions from the clinical point of view. Which, among them, contribute most to the genesis of diabetic renal damage? Which therapeutic interventions could prove effective and easy to achieve?
We have addressed these issues by concentrating our efforts on a unique hypertensive, type 2 diabetic rat model with nephropathy (SHR/NDmcr-cp).
HYPERTENSIVE, TYPE 2 DIABETIC RAT MODEL
SHR/NDmcr-cp has the genetic background of the spontaneously hypertensive rat (SHR) and thus becomes hypertensive.1,2 In addition, a mutation of the leptin receptor generates obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia, all of which characterize human type 2 diabetes. Eventually, this obese, diabetic rat develops significant renal damage, in agreement with our common clinical experience that hypertension plus metabolic derangements accelerate markedly diabetic renal damage.
We tested several therapeutic approaches in this model, that is obesity correction by caloric restriction, blood pressure normalization with antihypertensive drugs, glucose lowering by pharmacologic agents, and correction of hypoxia and of advanced glycation by novel approaches (Figure 1).
DIETARY CORRECTION OF OBESITY
Restriction of the caloric intake of SHR/NDmcr-cp by 30% for 20 weeks corrected both obesity and hyperlipidemia without changes in blood pressure, hyperglycemia, and hyperinsulinemia.2 Nevertheless, it prevented proteinuria and histological abnormalities of the kidney. Renoprotection was achieved in this model in association with a significant correction of obesity and hyperlipidemia but independently of hypertension, hyperinsulinemia, and hyperglycemia. Of note, renal damage correlated with body weight and with the renal content of advanced glycation end products (AGEs) and of oxidative stress.
NORMALIZATION OF BLOOD PRESSURE
The effect on the kidney of several types of blood pressure-lowering agents was then tested.1,3 An angiotensin receptor blocker (ARB), a calcium antagonist, or a beta-blocker was given for 20 weeks to SHR/NDmcr-cp. The agents normalized systolic blood pressure to the same extent, but only the ARB successfully decreased proteinuria. This finding fits with the clinical experience that renin-angiotensin system inhibitors provide a better renoprotection than other types of antihypertensives. Renal benefits appear independent of systemic blood pressure lowering and of changes in metabolic abnormalities.
The optimal doses of ARB needed for renoprotection and for blood pressure lowering were further defined.4 Above 120 mg/kg per day, a dose exceeding the level necessary for angiotensin II receptor saturation, the ARB valsartan (Diovan, Novartis) failed to further reduce blood pressure, a finding suggesting indeed complete blockade of angiotensin II receptor. Nevertheless, renoprotection witnessed by proteinuria progressed continuously in a dose-dependent manner, demonstrating further renal benefits of ARB independent of blood pressure lowering (our unpublished observation).
Impressively, ARB, but not calcium antagonist or beta-blocker, markedly reduced the renal AGE content despite no modification of the concomitant metabolic syndrome including hyperglycemia. Renal AGE content significantly correlated with proteinuria whatever the type of antihypertensive agent.3 ARB simultaneously corrected oxidative stress and hypoxia.3
CONTROL OF HYPERGLYCEMIA
The critical role of hyperglycemia in the genesis of diabetic renal injury is demonstrated by the fact that the strict glycemic control reduces microalbuminuria in diabetic patients with nephropathy.5 In addition, recent studies have implicated insulin resistance or hyperinsulinemia in its genesis.6 In this context, it is of interest to ask which agent provides a better renoprotection, insulin or an insulin sensitizer such as pioglitazone.
SHR/NDmcr-cp rats were given for 20 weeks either pioglitazone (Actos, Takeda) or insulin.7 Neither treatment modified hypertension. Pioglitazone aggravated obesity and provided poorer glycemic control than insulin but, in contrast with insulin, it significantly decreased plasma insulin levels. As a result, renoprotection was markedly better with pioglitazone than with insulin treatment as shown by proteinuria reduction. Both pioglitazone and insulin reduced the renal accumulation of AGEs and markers of oxidative stress, but only pioglitazone reduced renal expression of transforming growth factor (TGF)-beta.
Hyperinsulinemia and the attendant increase of TGF-beta expression might therefore prove useful therapeutic targets independently of glycemic control, a conclusion supported by clinical evidence that pioglitazone enhances renoprotection in obese, diabetic patients with nephropathy.8,9
HYPOXIA CORRECTION
Diabetic glomerular damage decreases the number of peritubular capillaries and thus oxygen diffusion to tubulointerstitial cells, leading to tubular dysfunction and fibrosis.10 The presence of chronic hypoxia in the diabetic kidney has been recently confirmed in experimental animals.3,11
Some mechanisms of the defense against hypoxia have been recently elucidated. In this phenomenon, the hypoxia-inducible factor (HIF) plays a crucial role.12 Its activation protects hypoxic tissues through the induction of a broad range of genes (eg, erythropoietin, vascular endothelial growth factor [VEGF], heme oxygenase [HO]-1, glucose transporter). Its stability relies on oxygen levels through its hydroxylation by prolyl hydroxylase (PHD). PHD functions as a sensor of hypoxia and as a negative regulator of HIF.
Cobalt inhibits HIF degradation by PHD by substituting for iron, an essential element for the PHD activity. We tested the role of HIF in diabetic nephropathy by providing cobalt for 20 weeks to our SHR/NDmcr-cp rats.13 It did not correct hypertension and metabolic abnormalities,14 but nevertheless reduced proteinuria as well as histological kidney injury. Expressions of HIF-regulated genes, including erythropoietin, VEFG, and HO-1 increased, whereas the renal expressions of TGF-beta and of advanced glycation were significantly reduced. Correction of hypoxia by PHD inhibitors15 may therefore protect the diabetic kidney, independently of metabolic status and blood pressure.
The recent demonstration, however,16 that both erythropoietin and VEGF independently accelerate diabetic retinopathy warrants caution. PHD has three isoforms and, fortunately, the respective role of each PHD has been elucidated. PHD2 primarily regulates angiogenesis and erythropoiesis.17,18 By contrast, the specific disruption of PHD1 induces hypoxia tolerance by reprogramming basal oxygen metabolism.19 A specific PHD1 inhibitor may therefore be an interesting candidate for future therapy in diabetic nephropathy.
AGE INHIBITION
Our animal experiments demonstrate that renoprotection does not necessarily rely on blood pressure or glycemic control but appears consistently associated with a decreased AGE formation and oxidative stress. The fact that insulin treatment prevents advanced glycation and oxidative stress without renoprotection is probably due to the persistence of hyperinsulinemia and its attendant overproduction of TGF-beta.
What are the mechanisms of AGE reduction? In vitro, ARB directly inhibits AGE formation,20,21 whereas insulin, pioglitazone, and cobalt are ineffective. The question thus arises as to whether a direct inhibition of AGE formation could protect against diabetic nephropathy. As previously mentioned, ARB is a potent AGE inhibitor both in vitro and in vivo. It protects the kidney, at least in part, independently of its blood pressure-lowering effect. We therefore designed a novel ARB derivative, R-147176, characterized by a marked inhibitory effect on oxidative stress, advanced glycation, and a minimal affinity for the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors and thus minimal antihypertensive effect.22
The inhibition of AGE formation, the affinity for the angiotensin 2 receptor, and the pharmacokinetic characteristics of 139 newly synthesized ARB derivatives were assayed, and R-147176 was eventually selected, as it strongly inhibited advanced glycation but was 6,700 times less effective than olmesartan (Benicar, Daiichi Sankyo) in AT1R binding. It was orally bioavailable and toxicologically safe. Despite a minimal effect on blood pressure, it provided significant renoprotection in SHR/NDmcr-cp as well as in Zucker diabetic fatty rats.22 The data clearly demonstrate that the renal benefits of ARB depend on the inhibition of AGE and oxidative stress by their chemical structure in addition to blood pressure lowering and AT1R affinity. Not only the kidneys but also the brains of experimental animals are protected by similar AGE inhibitory compounds.23,24
CONCLUSION
The current studies in SHR/NDmcr-cp rats disclose newer culprits in the pathogenesis of diabetic nephropathy. They may offer novel therapeutic targets. The future prevention of diabetic nephropathy and of its dramatic consequences will undoubtedly rely on a multipronged approach. The current therapies to correct classic factors (ie, obesity, hypertension, hyperglycemia, hyperinsulinemia) appear insufficient to fully prevent renal complications. These therapies should be supplemented by newer agents able to interfere with hypoxia, oxidative stress, advanced glycation, TGF-beta, and plasminogen activator inhibitor-1.25 Only time will tell us if a renewed approach suffices.
Toshio Miyata, MD, PhD, is from the Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, Sendai, Japan. He may be reached at t-miyata@mail.tains.tohoku.ac.jp. Charles van Ypersele de Strihou, MD, is from the Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium.
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