Growth hormone induces transforming growth factor-β1 in podocytes: Implications in podocytopathy and proteinuria

• Published in: Biochimica et biophysica acta. Molecular cell research 2023-02, Vol.1870 (2), p.119391-119391, Article 119391
• Main Authors: Mukhi, Dhanunjay, Kolligundla, Lakshmi P., Maruvada, Saikrishna, Nishad, Rajkishor, Pasupulati, Anil K.
• Format: Article
• Language: English
• Subjects: Animals; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Growth hormone; Growth Hormone - genetics; Growth Hormone - metabolism; Growth Hormone - pharmacology; Human Growth Hormone - genetics; Human Growth Hormone - metabolism; Human Growth Hormone - pharmacology; Humans; Kidney; Mice; Podocyte-proteome; Podocytes; Podocytes - metabolism; Proteinuria - genetics; Proteinuria - metabolism; SMAD pathway; TGF-β1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2022.119391

Pituitary growth hormone (GH) is essential for growth, metabolism, and renal function. Overactive GH signaling is associated with impaired kidney function. Glomerular podocytes, a key kidney cell type, play an indispensable role in the 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. Here we performed proteome analysis of the condition media from human podocytes and confirmed that GH-induces TGF-β1. Inhibition of GH/GHR stimulated-JAK2 signaling abrogates GH-induced TGF-β1 secretion. Mice administered with GH showed glomerular manifestations concomitant with proteinuria. 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. GH and TGF-β1 signaling components expression was elevated in the kidneys of human diabetic nephropathy patients. Our study identifies that GH induces TGF-β1 in podocytes, contributing to diabetic nephropathy. Growth hormone (GH) binding to GH receptor (GHR) activates Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 5 or 3 (STAT5/3), which eventually facilitate podocyte releasing transforming growth factor-β (Green podocyte/normal podocyte). Liquid chromatography followed mass-spectrometry analysis and identified the TGF-β1 isoform. Released TGF-β1 binds to the TGF-β receptor (TGF-βR) and activates the downstream SMAD pathway to induce SNAIL and other mesenchymal markers leading to podocyte dedifferentiation and proteinuria (Dark podocyte/dedifferentiated podocyte). [Display omitted] •Mature podocytes express functional GHR and JAK/STAT signaling components.•Growth hormone (GH) induces TGF-β1 isoform in podocytes.•GH activates SMAD signaling and alters podocyte permeability via TGF-β1.•Genetic deletion of GHR in podocytes protects mice from diabetic nephropathy.