More on renal disease progression: is interstitial inflammation truly protective?

P atients with a chronic glomerulopathy are at risk for progressively declining renal function that results in end-stage renal failure irrespective of etiology. The underlying pathophysiology is at least partly dependent on maladaptive functional changes that occur in the surviving nephrons upon destruction of a critical number of glomeruli. In proteinuric nephropathies, the dysfunction of the glomerular filtration barrier causes the abnormal passage of large amounts of potentially toxic plasma proteins and protein-bound molecules from the bloodstream into the tubular lumen. One widely accepted mechanism underlying the acceleration of progressive injury to the kidney is that the ensuing tubulointerstitial damage is induced by direct toxicity of filtered protein, because proteinuria has long been known to correlate with both the severity of glomerular barrier impairment and the rate of decline of renal function. An important question that has not yet been adequately addressed in this area is whether albumin in proteinuric ultrafiltrate may promote proximal tubule cell injury through enhanced endocytosis. The proximal convoluted tubule has a critical role in handling albumin and other filtered proteins in the mammalian kidney via its well-developed endocytic function. This field is rapidly expanding as a result of the identification of molecules that cooperate in receptor-mediated endocytosis at the brush border region. Megalin, a 600-kD glycoprotein that belongs to the LDL superfamily, is a multifunctional molecule that acts as a low-affinity receptor that mediates normal uptake of albumin and other filtered plasma proteins (1). Lack of megalin causes low molecular weight proteinuria in mice. In this issue of JASN, Theilig et al. (2) used mice with partial deficiency for megalin (megalin lox/lox;apoE Cre mice [Cre( )mice]) to assess whether megalin-dependent enhanced protein endocytosis by tubular epithelial cells would lead to upregulation of mediators that promote inflammation, tubular degeneration, and fibrosis. Megalin immunostaining shows a mosaic in these kidneys—that is, both megalin-positive and megalin-negative cells reside in tubules—with 60 to 80% of tubular profiles showing megalin deficiency in the mice that were used in this study. To assess effects of proteinuria on tubulointerstitial injury, anti–glomerular basement membrane glomerulonephritis (GN) was induced in megalin-deficient mice [Cre( )GN] and in control mice [Cre( )GN], and animals were killed on day 18 after injection of nephritogenic antiserum. Preliminary to discussion of the data, it should be acknowledged that this is an acute and immunologically mediated disease, making it difficult to infer to what extent the observations at this relatively early time point may apply to the pathophysiology of chronic proteinuria. A more prolonged exposure to proteinuria is usually needed for significant tubulointerstitial damage to ensue. For instance, in Adriamycin nephrosis, one of the most severe animal models of nephrotic proteinuria that invariably progresses to glomerulosclerosis and tubulointerstitial injury, mild tubulointerstitial changes develop only after 1 mo. Moreover, in this model, the deficiency of megalin was incomplete within individual nephrons. In proteinuric mice, only megalin-positive cells were engaged in protein endocytosis, as revealed by immunostaining for mouse IgG, which permitted differences in the localization of marker molecules of interest to be compared in megalindeficient and -sufficient cells. However, it can be difficult to draw inferences from the topographic relation with interstitial changes, particularly when they involve mediators that can diffuse from their site of origin along the nephron toward the contiguous interstitial compartment. Nephritic mice that lacked megalin developed both proteinuria and glomerular crescentic lesions, resulting in tubular obstruction and degeneration. The phenotype of the animal model of partial megalin deficiency included worse glomerular injury in response to anti–glomerular basement membrane serum. Therefore, it is possible that more glomerular damage could have overwhelmed any potential protective effect of tubular megalin deficiency. Nevertheless, one major finding was that the expression of the proinflammatory and fibrogenic molecules endothelin-1, TGF1, and TGF3 was increased exclusively in megalin-positive cells. This is in agreement with available in vitro data showing upregulation of such molecules by proximal tubular cells in response to protein load (3–8) and suggests that the stimulatory effect could be mediated by megalin. Intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 showed a similar pattern, whereas the upregulation of monocyte chemoattractant protein-1 was variable. Published online ahead of print. Publication date available at www.jasn.org.