RAGE Knockout Reduces Age-Related Kidney Damage in Mice

RAGE is the receptor for advanced glycation end-products (AGEs), the mechanism by which cells react to the presence of AGEs. AGEs are metabolic byproducts that are both created in the body and present in the diet; cooking animal fat produces AGEs, for example. Diets heavy in meat and the related, fun, unhealthy products so prevalent in this modern calorie-packed world of ours are also heavy in AGEs of various sorts. It remains a topic for discussion as to the degree to which dietary AGEs are a problem, however. Do they contribute significantly to the issues caused by AGEs in general, or only in conditions in which metabolism is already aberrant, such as metabolic syndrome and type 2 diabetes? Opinions differ.

There are two quite distinct classes of harm associated with AGEs in aging. The first, and not the topic of today’s research, is the creation of persistent cross-links in the extracellular matrix by the AGE glucosepane. A cross-link shackles together two of the complex molecules the extracellular matrix, thereby altering its properties by preventing free movement of those molecules. Significant cross-linking degrades elasticity, strength, and other necessary properties of various tissues. In the case of blood vessels, this loss of elasticity leads to hypertension and consequent cardiovascular disease. Glucosepane cross-links cannot be effectively broken down by our biochemistry, and thus will have to be dealt with via some form of therapy.

The second form of harm associated with AGEs is chronic inflammation. Chronic inflammation causes disarray and damage throughout the body, degrading tissue maintenance and encouraging dysfunction in organs and biological systems. AGEs produce inflammation in part by their interaction with RAGE, triggering it relentlessly and thus spurring other inflammatory signaling. The more AGEs there are in circulation, even if they are short-lived varieties, easily dealt with by the body, the more inflammation. Metabolic disorders of obesity, such as the aforementioned metabolic syndrome and type 2 diabetes, are characterized by excessive AGEs and excessive inflammation – though it is worth noting that there are plenty of other ways by which excess fat tissue generates inflammation.

Here, researchers demonstrate that the burden of inflammation and resulting organ damage occurring due to a raised level of AGEs is reduced when RAGE is disabled. The study uses normal and genetically engineered mice lacking RAGE, the mice fed either a normal diet or a diet containing large amounts of dietary AGEs. To the point I raised above about opinions on the effects of dietary AGEs, choice of diet didn’t make much difference here. But RAGE knockout mice are better off in old age in either case, most likely due to reduced inflammatory consequences arising from the AGE-RAGE interaction.

Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions

The impact of advanced glycation end-products (AGEs) on chronic kidney disease (CKD), especially through binding to their main receptor RAGE (receptor for AGEs), has received significant research attention. The AGEs form a heterogeneous group of molecules resulting from permanent binding of reducing sugars to a range of amino-compounds. Their endogenous formation occurs under various conditions such as hyperglycemia and oxidative stress, but also aging. Their presence is moreover clearly identified in foods: daily intake of Nɛ-carboxymethyllysine (CML, the most studied AGE) can be as high as 252 µg/kg body weight in a typical European diet.

Evidence has recently accumulated incriminating the endogenous AGE/RAGE axis in age-related diseases. RAGE is a multiligand, transmembrane receptor activating major pro-inflammatory and pro-oxidative signaling pathways. Its expression in numerous cell types increases with aging and pathological conditions such as diabetes, but a role for this receptor has been postulated in the premature dysfunction of several organs, even in the absence of diabetes. The impact of chronic exposure to dietary AGEs on aging remains poorly studied, however.

Considering the preferential accumulation of CML in the kidneys under a CML-enriched diet and studies linking dietary AGEs and kidney damage, we hypothesized that kidneys are target organs for accelerated aging induced by AGE/RAGE interactions. In order to study this question, histologic markers of renal aging were analyzed in 2-month-old male wild-type (WT) and RAGE knockout mice fed a control or a CML-enriched diet over 18 months.

Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE knockout mice, with a predominantly tubular localization. The CML-rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE knockout mice were significantly protected against nephrosclerosis lesions and renal senile apolipoprotein A-II (ApoA-II) amyloidosis. Compared with old WT mice, old RAGE knockout mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE knockout mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE-/- mice, suggesting RAGE is an important receptor in so-called inflammaging.

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