Pituitary growth hormone (GH) is essential for growth, metabolism, and renal function. Elevated plasma GH levels in type I diabetes and acromegaly are associated with impaired kidney function. Glomerular podocytes, an essential kidney cell type, play an indispensable role in renal filtration and express GH receptors (GHR), suggesting the direct action of GH on these cells. However, the precise mechanism and the downstream signaling events by which GH leads to diabetic nephropathy remain to be elucidated. We performed unbiased RNA-seq and proteomic analysis to investigate the pathobiology of GH on podocyte biology. RNA-seq analysis revealed elevated TNF-α signaling in GH-treated human podocytes. Conditioned media from GH-treated podocytes induced the differentiation of monocytes to macrophages. Interestingly, the neutralization of conditioned media with the TNF-α antibody attenuated its ability to differentiate monocytes. Treating mice with GH increased macrophage recruitment, podocyte injury, and proteinuria. Further, we performed proteomic analysis of the condition media from human podocytes and confirmed that GH induces TGF-β1. Inhibition of GH/GHR stimulated-JAK2 signaling abrogated TGF-β1 secretion. Pharmacological inhibition of TGF-βR1 in mice prevented GH-induced TGF-β dependent SMAD signaling and proteinuria. Conditional deletion of GHR in podocytes protected mice from streptozotocin-induced diabetic nephropathy. Furthermore, we noticed the activation of TNF-α and TGF-β1 signaling and fibrosis in DKD patients' kidney biopsies. Targeting GH-signaling in diabetic patients could be a therapeutic approach to prevent chronic kidney disease.

Dr. Anil Pasupulati is Associate Professor at the Department of Biochemistry, University of Hyderabad. Anil received his Ph.D. from ICMR-NIN, Hyderabad in 2008 and worked as postdoctoral fellow at University of California and University of Michigan for 4 yrs. In 2012 he received DBT-Wellcome trust Early Career Fellowship (India) and DST-INSPIRE Faculty Award (India). He served as an Assistant professor at Osmania University from 2012-14 and moved to University of Hyderabad in 2014.  His research interests are: Diabetic nephropathy, Chronic Kidney Disease, and Bioinformatics of Kidney.