Albumin Degradation in the Diabetic Kidney
A major long-term complication of diabetes is kidney damage that leads to diabetic nephropathy (DN), a condition associated with considerable morbidity and mortality among diabetic patients. An early sign of DN is the appearance of protein, primarily albumin, in the urine. Indeed, clinicians have used urinary albumin for years to monitor the onset and progression of DN. More recently, however, researchers have noted that the urine of DN patients contains not only intact albumin molecules, but also albumin fragments. This has led them to question the origin of these fragments. Do they result from degradation of albumin in the urine, or in the blood, or in the kidney itself, and what can their origin tell us about the pathogenesis of DN? To answer this question, Vanderbilt Basic Science investigator Richard Caprioli, along with his collaborators Billy Hudson and Raymond Harris (Department of Medicine) and their laboratories to use matrix-assisted desorption/ionization imaging mass spectrometry (MALDI-IMS) to search for the presence of albumin fragments in the DN kidney. MALDI-IMS is a technique that enables both the identification and localization of proteins and other molecules present in a tissue slice. The researchers carried out their investigation using kidneys of eNOS-/- db/db mice, a well-characterized model of DN. Their data demonstrated the presence of albumin fragments in the DN kidneys but not in healthy control kidneys. The amount of the fragments, which were found primarily in the tubules of the kidney, correlated with the severity of DN. Sequence information derived from the data suggested that the enzyme most likely responsible for albumin degradation was the lysosomal protease cathepsin D. Consistently, the investigators found increased levels of cathepsin DN in the proximal tubule cells of DN kidneys as compared to those of normal kidneys. The findings suggest that albumin in the tubules of DN kidneys is taken up by the cells, partially degraded in lysosomes, and then returned to the tubule lumen for excretion in the urine. Thus, it appears that albumin fragmentation is an intrinsic characteristic of DN pathogenesis, a conclusion supported by the finding that treating eNOS-/- db/db mice with pyridoxamine to ameliorate DN lesions results in reduced albumin fragmentation. The findings provide new insights into mechanisms of kidney damage in DN and suggest the possibility that albumin fragmentation can be used as a biomarker of DN initiation and progression. The work is published in the journal Kidney International [K.J. Grove, N.M. Lareau, et al. (2018) Kidney Int., published online May 17, doi: 10.1016/j.kint.2018.01.040].