Peritubular Ischemia Contributes More to Tubular Damage than Proteinuria in Immune-Mediated Glomerulonephritis

Abstract

Proteinuria is a key factor in the progression of tubulointerstitial injury. Recently, tubular ischemia as a result of loss of peritubular capillaries has been identified as another major contributor to disease progression, but the relative contribution of these insults on tubulointerstitial damage is unknown. Anti-glomerular basement membrane glomerulonephritis was induced in wild-type (WT) and Fc receptor knockout (FcRKO) mice, which have been shown to be relatively protected against glomerular endothelial injury. Despite comparable degrees of proteinuria, WT mice developed significantly worse renal function than FcRKO mice, along with higher expression of both type I collagen and kidney injury molecule-1 (a sensitive marker of acute tubular injury) by real-time PCR and immunohistochemistry. In addition, compared with FcRKO mice, WT mice exhibited a greater decrease in peritubular red blood cell velocity by intravital videomicroscopy and a marked increase of tissue hypoxia. In vitro, kidney injury molecule-1 expression increased in cultured mouse proximal tubular epithelial cells in response to cellular stresses, including hypoxia, starvation, and exposure to excessive protein; therefore, it is suggested that hypoxic insults more strongly influence tubulointerstitial damage than proteinuria alone in models of subacute renal disease.

Effect of treatment on urinary kidney injury molecule-1 in IgA nephropathy

“…showed treatment with an ARB reversed tubular Kim-1 expression in an adriamycin induced nephropathy model [21]. In several other experimental models, ARBs produced renal structural improvement [23-25]. These studies suggest that RAS blockade can improve tubulointerstital damage and decrease urinary Kim-1, a marker of tubular damage.…”

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

“…In progressive autologous/accelerated form of anti-glomerular basement membrane glomerulonephritis in mouse, rarefaction of peritubular capillaries causes peritubular ischemia that is responsible for tubulointerstitial damage, even more than proteinuria. 34 Here, anti-glomerular basement membrane antiserum was administered over 3 consecutive days, inducing also a severe accelerated form of glomerulonephritis. This model thus differs from that described in our previous study of calpain regulation 8 where a single injection of antiglomerular basement membrane antiserum caused a transient heterologous form of glomerulonephritis.…”

A Rare Case of Type I RenalTubular Acidosis with Membranous Nephropathy Presenting as Hypokalemic Paralysis

“…Glomerulus-derived cytokines activating tubular epithelial cells reduce peritubular blood flow, leading to tubulointerstitial ischemia and hyperfunction of remnant tubules. Peritubular ischemia contributes more to tubular damage than proteinuria in immune-mediated glomerulonephritis [7]. Occasionally, the same inflammatory mechanism of glomerulonephritis may also affect the tubules.…”