Abstract
The kidney is an insulin-sensitive organ involved in glucose homeostasis. One major effect of insulin is to induce glycogen storage in the liver and muscle. However, no significant glycogen stores are detected in normal kidneys, but diabetic subjects present a characteristic renal histopathological feature resulting from extensive glycogen deposition mostly in nonproximal tubules. The mechanism of renal glycogen accumulation is yet poorly understood. Here, we studied in situ glycogen accumulation in the kidney from diabetic IRS2-knockout mice and the effect of the insulin-mimetic agent sodium tungstate (NaW). IRS2-knockout mice displayed hyperglycemia and hyperinsulinemia. NaW only normalized glycemia. There was no evident morphological difference between kidneys from untreated wild-type (WT), NaW-treated WT, and untreated IRS2-knockout mice. However, NaW-treated IRS2-knockout mice showed tubular alterations resembling clear cells in the cortex, but not in the outer medulla, that were correlated with glycogen accumulation. Immunohistochemical detection of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, mostly expressed by renal proximal tubules, showed that altered tubules were of proximal origin. Our preliminary study suggests that IRS2 differentially regulates glycogen accumulation in renal tubules and that NaW treatment in the context of IRS2 ablation induces abnormal glycogen accumulation in cortical proximal tubules.
Highlights
Insulin participates in a wide spectrum of growth and metabolic responses by binding to the insulin receptor (IR) and inducing IR tyrosine kinase activity to phosphorylateIR itself and several other proteins, among them IR substrates (IRS) [1]
No differences were detected between untreated WT (WT), treated WT (NaW-WT), and untreated IRS2-KO (IRS2-KO) kidneys with or without α-amylase digestion (Figures 1(a)–1(f), resp.), indicating that no significant glycogen stores were present in these conditions, despite hyperglycemia in IRS2-KO mice
Hematoxylin/eosin staining confirmed that no significant differences in kidney morphology were evident between WT, NaW-WT, and IRS2-KO mice (Figures 1(i)–1(k), resp.), but kidneys from NaW-IRS2-KO mice showed a distinctive pattern of tubular morphology (Figure 1(l))
Summary
Insulin participates in a wide spectrum of growth and metabolic responses by binding to the insulin receptor (IR) and inducing IR tyrosine kinase activity to phosphorylateIR itself and several other proteins, among them IR substrates (IRS) [1]. Contrary to the liver and muscle, no significant glycogen stores are detected in the kidney under normal conditions, but diabetes induces abnormal glycogen deposition especially in nonproximal tubular epithelial cells [7,8,9,10]. This pathological feature has long been recognized, but the triggering mechanisms are not fully understood, albeit overexpression and activation of GS may be involved [8, 9]
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