Letter to the Editor: “Insulin Resistance, the Renin-Angiotensin System, and Associated Renal Injury: Is Insulin Resistance the Culprit?”

The clustering of insulin resistance, dysglycemia, dyslipidemia, hypertension, and central obesity represent the major features of metabolic syndrome. These clusters of factors may share a common etiology, and each of them is a risk factor for cardiovascular disease. The metabolic syndrome appears to affect between 10–25% of the adult populations worldwide. Several studies have described the association between metabolic syndrome and diabetes and cardiovascular disease.[1] Although obesity is often associated with diabetes and hypertension, which are two of the most common risk factors for the development of end-stage renal disease (ESRD), it has been suggested that obesity per se is an independent risk factor. Prospective data also suggest that the presence of the metabolic syndrome is independently related to a greater risk of developing chronic kidney disease.[2] Furthermore, in different analyses of subgroups of the third National Health and Nutrition Examination Survey (NHANHES III) population, elevated insulin resistance as well as the presence of the metabolic syndrome were independently associated with an increase in the prevalence of chronic kidney disease.[3],[4] Recently, the increase in body mass index was regarded as an independent predictor for ESRD after adjusting for blood pressure and the absence or presence of diabetes.[5] The relation between the metabolic syndrome and the risk for kidney disease can be greatly explained by the fact that most of the basic components of the metabolic syndrome—namely, type 2 diabetes, hypertension, obesity, and low high-density lipoprotein cholesterol levels—apart from predisposing to cardiovascular disease, are also risk factors for chronic kidney disease.[4] A number of potential mechanisms were hypothesized to be involved in insulin resistance induced renal injury. Among them are increased oxidative stress, increased expression of growth factors (IGF-1,TGF-β), and alteration in the production of renal nitric oxide (NO). Importantly, insulin resistance is associated with the significant activation of the renin-angiotensin system.[3–5]

Mediators involved in metabolic syndrome-induced renal injury are poorly understood, and most of the available information comes from fatty Zucker rat studies,[6] an animal model of genetic obesity that results from inactivating mutation in leptin receptor gene. Homozygous Zucker rats (fa/fa) exhibit most of the metabolic picture seen in human obesity, including hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, and proteinuria. These animals also develop glomerular hypertension, hypertrophy, and sclerosis, and often die from ESRD.[6] The mechanism by which renal disease is produced in obese Zucker rats is largely unknown, but it has been shown that nephropathy associated with obesity in the obese Zucker rat model could be associated with the activation of the renin-angiotensin system. Furthermore, in vitro studies have shown that insulin is necessary for the angiotensin-II-induced contraction of the mesangial cells.[7] Hyperinsulinemia was shown to be associated with a significant increase in both aldosterone and pressor responses to infusion of angiotensin II.[8] Importantly, insulin has stimulatory effect on the angiotensin production from hepatic cells, the main source for the RAS.[8] Interestingly, Ahmed et al. concluded that there is a strong association between increasing body mass index and the increase in the activity of RAS, and that this may be a mechanism by which obesity contributes to renal disease. Their study showed that in the renal plasma flow response to captopril, as an index of renin-angiotensin system activity, in 100 subjects (body mass index [BMI] exceeded 25 Kg/m² in 56 patients and 30 Kg/m² in 22 patients), there was a significant vasodilator response to captopril, even after adjusting for age and BMI.[9] Interestingly, weight loss in obese patients (i.e., a BMI reduction from 48 to 32 after one year) has resulted in significant improvement in renal hemodynamic abnormalities associated with severe obesity (i.e., augmented GFR, RAS, and albuminuria.[10] It is not yet clear how insulin resistance modulates the RAS. Whether or not the increased level of RAS activity observed in these two studies persists after weight loss is unclear. It's important to emphasis that, given the many health benefits already associated with weight loss, weight reduction should be advised in overweight and obese patients. Based on current data, however, it is not yet clear whether the administration of RAS-blockade agents in overweight or obese individuals with or without other features of the metabolic syndrome will be a potential therapeutic strategy in this growing number of patients. Importantly, it is unclear how this will reduce the prevalence of epidemic of ESRD. Overall, a pathway linking insulin resistance and hyperinsulinemia with renal injury through the activation of RAS at this stage can only be speculated, and many aspects of this association need to be further elucidated.