Abstract
BackgroundDiabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models.MethodsThis study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. Mice with cell‐targeted overexpression of TIMP3 in myeloid cells (MacT3), podocyte‐specific ADAM17 knockout mice (∆PodA17), and DBA/2J mice, were rendered diabetic at 8 weeks of age with a low‐dose streptozotocin protocol. DBA/2J mice were administered new peptides based on the human TIMP3 N‐terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24‐hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid‐shift staining, and Real Time‐PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex.ResultsOur results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4), and the improvement of podocyte structural markers such as WT1, nephrin, and podocin. Moreover, the positive effects were exerted through a mechanism independent from glycemic control.ConclusionsIn diabetic mice the targeting of TIMP3 system improved kidney structure and function, representing a valid approach to develop new avenues to treat this severe complication of diabetes.
Highlights
Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function
The results showed that weeks after STZ administration, % ( / ) of wt mice exhibited hyperglycemia compared to % ( / ) of MacT mice, indicating that Tissue Inhibitor of Metalloproteinase (TIMP) overexpression in cells of the myeloid lineage significantly reduced
Obtained results indicated that after weeks of hyperglycemia, mice showed the same rate of diabetesinduced CD positive cells infiltration in renal cortex (Figure S ), diabetic MacT mice showed increased TIMP mRNA expression (p < . ) (Figure B) and developed significantly less albuminuria compared with the diabetic wt mice (p < . ) (Figure C)
Summary
Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Tissue Inhibitor of Metalloproteinase (TIMP ) is an ExtraCellular Matrix (ECM)-bound protein that is broadly expressed in humans and mice and is involved in a wide range of physiological processes, such as cell growth and migration, angiogenesis and apoptosis. MMP has been shown to be involved in dedifferentiation of podocytes and renal tubular cells in diabetic mice, and its expression is increased in glomeruli from diabetic patients.
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