An increase in glomerular filtration rate (GFR) in early type 1 diabetes is a risk factor for progression to end- stage renal disease. Preventing or treating early glomerular hyperfiltration may reduce kidney damage and prevent kidney failure. Our work indicates that early glomerular hyperfiltration can be the consequence of kidney growth. This growth is accompanied by an abnormal increase in proximal tubule salt reabsorption whereby less salt reaches the macula densa resulting in activation of tubuloglomerular feedback, increased GFR and hyperfiltration. Further, aberrant proximal tubule reabsorption causes the salt paradox, with a high salt intake decreasing GFR. But is kidney growth alone sufficient to account for the progression of diabetic complications? Early growth of the diabetic proximal tubule begins as a mitogen-induced growth response followed by cyclin kinase inhibitor mediated G1 cell cycle arrest, i.e., initial hyperplasia followed by hypertrophy. This mechanism resembles that of senescence. We hypothesize that a senescent-like arrest of the proximal tubules in diabetes would affect the state of cell differentiation and responsiveness. A change in response to salt reabsorption would form the basis not only for basal glomerular hyperfiltration but also for the salt paradox. Using senescent fibroblasts as a paradigm, senescent proximal tubule cells would display increased oxidative stress, adding to the diabetic inflammatory environment, reduced proteolytic activity that would promote later stage diabetic hypertrophy, and skewed extracellular matrix production and remodeling that would contribute to fibrosis. We hypothesize that a senescent-like arrest/phenotype of cortical tubule cells is a contributing factor not only to hyperfiltration, but to other downstream diabetic complications. Gene knockout will be used to modulate early diabetic kidney growth/hypertrophy. We will evaluate the consequences on the senescent-like arrest/phenotype of cortical tubules, basal tubular hyperreabsorption and glomerular hyperfiltration, and the salt paradox via molecular and physiologic parameters. ? ?
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