Severe proteinuria, sustained for 6 months, induces tubular epithelial cell injury and cell infiltration in rats but not progressive interstitial fibrosis

Abstract

We succeeded in developing a model of persistent nephrosis without severe glomerular abnormalities, nephrectomy or other manoeuvres known to induce disturbed haemodynamics, using an agent without tubulointerstitial toxicity, and considered it to be suitable for investigating the direct toxicity of proteinuria. In this model, isolated massive proteinuria induced interstitial injury. However, the degree of injury was suggested to be much less than that observed in other previously developed models.

How Does Proteinuria Cause Progressive Renal Damage?

“…It is likely that filtered proteins other than or in addition to albumin induce tubular dysfunction and injury in conditions of nonselective proteinuria, in which large molecular weight proteins are a significant component. In contrast, relatively selective albuminuria induces delayed mononuclear cell infiltration (53) and usually is associated with no or mild chronic tubulointerstitial injury. In this respect, the case of minimal-change disease has been considered sometimes an exception to the rule that interstitial infiltrates develop with time in proteinuric glomerulopathies.…”

The Role of Tubulointerstitial Inflammation in the Progression of Chronic Renal Failure

“…These mechanisms may act in combination but their role in the progressive scarring of the kidney has not been fully elucidated. Each one in isolation provides insufficient explanation for chronic renal disease progression; tubular encroachment by misdirected filtrate does not extend to adjacent nephrons [5], interstitial accumulation of macrophages and lymphocytes in the overload proteinuria model does not lead to chronic renal damage [42] and long-standing proteinuria in cubilin-deficient patients (Imerslund-Gräsbeck syndrome) is not associated with renal functional impairment [43]. Nevertheless, as shown in table 1, many interventions addressed to mechanisms discussed in this review have proven beneficial in models of nonimmune experimental renal disease.…”

Proteinuria as a Mediator of Tubulointerstitial Injury

“…An interesting model of glomerular epithelial cell injury has been recently induced in rats by multiple injections of monoclonal antibody against a slit diaphragm protein (MoAB 5-1-6). Despite minimal or no ultrastructural damage to the podocyte, a consistent finding in these rats was the presence of proteinuria that was both highly selective and invariably associated with significant interstitial infiltration of T cells and macrophages detected several weeks after the first injection of antibody [19].…”