Podocyte-Specific GLUT4-Deficient Mice Have Fewer and Larger Podocytes and Are Protected From Diabetic Nephropathy

Abstract

Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

“…However, in brown adipocytes, insulin-mediated glucose transport and GLUT4 translocation are through IRS2, suggesting that podocytes and adipocytes display similar requirements of IRS2 in respect to insulin stimulated activation of AKT, GLUT4 translocation and glucose uptake [40]. Interestingly, it has recently been shown that there are insulin-independent roles of GLUT4 in podocytes that modulate their size and number [41], although it is unknown if these effects are modified by the IRS family. It is also clear that AKT2 has an important role in podocytes viability [30].…”

The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes

“…Insulin and muscle contraction are the major known mediators of GLUT4 translocation under physiological conditions [40,41]. The importance of podocyte insulin signaling in the pathogenesis of diabetic kidney disease is suggested by the observation that podocytes isolated from diabetic db/db mice cannot phosphorylate Akt in response to insulin and do not translocate GLUT4 to the plasma membrane after insulin stimulation [42]. We suggest that insulin induces the TRPC6-dependent entry of Ca 2+ into podocytes, the translocation of GLUT4 to the membrane, and, consequently, an increase in glucose uptake in podocytes.…”

The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes

“…Patients with mutations in genes encoding different mitochondrial enzymes, such COQ2, COQ6, COQ10, and aarF domain-containing kinase 4 (ADCK4), present with podocyglomerulosclerosis, even in the absence of hyperglycemia (7). The effect of insulin receptor deletion appears to be independent of glucose uptake, as mice with podocyte-specific deletion of glucose transporter type 4 (Glut4) do not develop similar changes (8). Insulin-induced activation of AKT acts as an important regulator of cytoskeletal changes and prosurvival factor in podocytes and might explain the strong phenotype develop- The bigger picture…”