JAK-STAT pathway activation compromises nephrocyte function in a Drosophila high-fat diet model of chronic kidney disease

ABSTRACT Chronic kidney disease is a major health issue and is gaining prevalence. Using a Drosophila model for chronic kidney disease, we show that a high-fat diet (HFD) disrupts the slit diaphragm filtration structure in nephrocytes, the fly functional equivalent of mammalian podocytes. The structural disruption resulted in reduced filtration function in the affected nephrocytes. We demonstrate that HFD activates the JAK-STAT pathway in nephrocytes, which has previously been linked to diabetic kidney disease. JAK-STAT activation was initiated by increased expression and release of the adipokine, Upd2, from the fat body. This leptin-like hormone is a known ligand of JAK-STAT. Both genetic and pharmacological inhibition of JAK-STAT restored nephrocyte HFD-associated dysfunction. Altogether, our study reveals the importance of the JAK-STAT signaling pathway in the adipose tissue−nephrocyte axis and its contribution to HFD-associated nephropathy. These findings open new avenues for intervention in treating diabetic nephropathy and chronic kidney disease. HIGHLIGHTS High-fat diet (HFD) disrupt nephrocyte slit diaphragm structure and filtration HFD releases fat body adipokine, Upd2, which activates JAK-STAT in nephrocytes Genetic/pharmacological inhibition of JAK-STAT reverses HFD nephrocyte dysfunction JAK-STAT signaling mediates adipose-nephrocyte axis in HFD-associated nephropathy IMPACT STATEMENT Using a Drosophila model for chronic kidney disease, Zhao et al. show that a high-fat diet induces excretion of a leptin-like JAK-STAT ligand from the fat body. Thus, driving the adipose-nephrocyte (podocyte equivalent) axis through activated JAK-STAT signaling. These findings link obesity to kidney disease, implicating new avenues for therapeutics.