Hypothesis: Chronic Progressive Nephropathy in Rodents as a Disease Caused by an Expanding Somatic Mutant Clone

Chronic progressive nephropathy is a common noninfectious disease in aging (mice, rats) and non-aging (naked mole rat) rodents, sometimes resulting in death. The etiology and pathogenesis of the disease remain mysterious. For instance, it remains unclear what is the immediate cause of the disease and where exactly in the kidneys, glomerular or tubulointerstitial compartment, do primary and secondary changes occur. Here, I propose a potential scenario for development of progressive nephropathy that is based on an assumption that the disease is caused by occurrence and spread of mutant cellular clones from tubular epithelium secreting proinflammatory and prosclerotic cytokines. The hypothesis considers some features of the disease that have never been discussed earlier. According to the proposed concept, a clone of mutant cells secretes cytokines inducing chronic inflammation, proliferation of fibroblasts, and active collagen production that eventually results in sclerosis and thickening of tubular basement membranes. Sclerosis of interstitium and thickening of tubular basement membranes cause narrowing of some parts of the nephron, especially collecting ducts, which hinders passage of the urine, elevates tubular hydrostatic pressure, and impairs filtration and reabsorption in the kidneys. High hydrostatic pressure and reabsorption-induced elevated concentration of macromolecular substances in the primary urine result in development of large cysts and glomerular hyalinosis followed by renal failure. Based on this, it might be concluded that chronic progressive nephropathy in rodents represents a special type of tubulointerstitial dysplasia (or "non-tumorous neoplasia") in kidneys with secondary glomerular disorder at late stage of the disease. The concept for development of the disease proposed here may be of special importance from the viewpoint of toxicological pathology and gerontology, particularly for analysis of pathological features resulting in death of non-aging animals (naked mole rats).