Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Abstract

Activation of the JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2–3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.

B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacement

“…A pathogenic role for cytokine signaling in proteinuric diseases is supported by a recent publication describing a transgenic mouse overexpressing JAK2 in podocytes (48). When crossed with the Akita diabetic nephropathy mouse model infused with angiotensin II, enhanced proteinuria was observed that was largely reversed with JAK2 inhibition.…”

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

“…Human glomerular MCs express NADPH oxidase and activates protein kinase C, mitogen activated protein kinase, and nuclear factor-jB (NF-jB) which eventually results in overproduction of extracellular matrix proteins [27]. Excess fibroblasts infiltrate the interstitium with consequent progressive interstitial fibrosis [28]. Hyperglycemia triggers increased intracellular fibroblast growth factor 23 (FGF23) is a phosphatonin responsible for renal phosphate elimination.…”

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

“…Similarly, whole body GHR/ binding protein (BP) gene disruption protected mice against the development of DN [7]. Mice overexpressing JAK2, an immediate target of GH/GHR axis in podocytes resulted in thickening of GBM and foot process effacement [27]. Therefore, we hypothesized that targeted deletion of GHR in podocytes may prevents renal hypertrophy and proteinuria in experimental diabetic mice.…”