Microalbuminuria and Proximal Tubule Remodeling in the Cardiometabolic Syndrome

Abstract

Microalbuminuria is a simple screening test that is not only associated with an increased risk of progressive renal insufficiency, but also an increased risk of cardiovascular disease and stroke in the cardiometabolic syndrome. The role of oxidative stress, inflammation, and cellular-extracellular matrix remodeling fibrosis is very important, and the authors have previously observed that albuminuria is related, in part, to loss of the integrity of the glomerular filtration apparatus. The proximal tubule may play a more important role than previously thought, as it is estimated that in health this portion of the nephron reabsorbs 5-8 g of albumin that normally leaks through the glomerulus on a daily basis. Recently, the authors have made important preliminary observational findings regarding proximal tubule microvilli remodeling and oxidative stress, which may help to explain microalbuminuria. These observations suggest that albuminuria is associated with proximal tubule injury, as well as loss of integrity of the glomerular filtration barrier in association with obesity and insulin resistance.

Albumin Activation of NAD(P)H Oxidase Activity Is Mediated via Rac1 in Proximal Tubule Cells

“…The PTC primarily act to reabsorb albumin via a Rac1-mediated receptor endocytosis in normal ranges from glomerular loss that, in excess, may lead to concurrent Rac1 activation of NAD(P)H oxidase and resultant in ROS formation [4, 8, 16, 26]. Consistent with this notion, we observed albumin-stimulated Rac1 translocation and GTP activation with increases in NAD(P)H oxidase activity and ROS formation (fig.…”

“…Recent evidence identifies Rac1 as an important activator of receptor-mediated albumin endocytosis in the PTC [6]. Recently, the concept has been developed that in pathophysiological states of albumin overload in the PTC, the excess filtered albumin exerts direct toxicity on the PTC via increased Rac1 activation, mediating a receptor endocytosis and concurrent NAD(P)H oxidase activation and ROS formation [8,9,10,11,12]. …”

Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats

“…In this regard, β-adrenergic receptor blockers suppress the SNS tissue response and renal secretion of renin [32,33]. These data facilitate the notion that β-blockers could reduce PTC injury and remodeling in scenarios involving both RAS and SNS activation such as exists in the transgenic Ren2 rat that manifests progressive albuminuria [3,7,26]. …”

“…This process is disrupted by elevated tissue levels of Ang II. Albumin retrieval can be restored through Ang II blockade [7,9,10,11,12,13,14,15,16,17,18,19,20]. Smaller quantities of filtered proteins that are not retrieved undergo lysosomal degradation before urinary excretion as small peptide fragments [17,21].…”

“…Microalbuminuria is an important early clinical indicator of progressive kidney disease in association with the metabolic syndrome and diabetes [1,2,3]. PTCs normally reabsorb most of the glomerular-filtered protein, so only 30 mg or less appears in the urine [7,8,9,10,11,12,13,14]. Further, there is increasing evidence that growth factors such as angiotensin II (Ang II), in conjunction with filtered proteins, can exert direct injury to the PTC resulting in tubulointerstitial fibrosis.…”