A study by Anil K Pasupulati, Assistant Professor at Department of Biochemistry, School of Life Science, University of Hyderabad (UoH) and his team has showed that Reactivation of Embryologically Active Events contributes to Diabetic Nephropathy.

Diabetes is a major cause of kidney failure, blindness, heart attacks, stroke and amputation of lower limbs. Diabetes is one of the leading causes of death worldwide. Diabetic nephropathy is one of microvascular complication that arises as a consequence of hyperglycemic milieu. Diabetic nephropathy is characterized by moderate to heavy proteinuria and degeneration of renal tissue. In healthy individuals, glomerular podocytes (present in nephron) are intact and offer glomerular permselectivity thus curb protein loss in the urine.  Nevertheless, the molecular cues that manifest in podocyte injury and protein loss in diabetic nephropathy have largely remained unknown.

Several embryologically active signaling events remain silent in adult life. However, reactivation of those events in the mature adults manifests in the progression of diseases such as cancer and diabetes. Dr. Anil’s laboratory is interested in understanding the mechanism of how pathological events trigger and implicated in the pathogenesis of diabetic nephropathy. Diabetes is presented with elevated levels of glucose, AGEs, and growth hormone, etc. Employing immortalized human podocytes as a model we found that several transcription factors and co-activators (ZEB2, WT1, and NICD1) get overexpress during diabetic nephropathy, reactivate embryologically active events thus contribute to the glomerular diseases. Podocytes are terminally differentiated visceral epithelial cells and contribute to the glomerular permselectivity. Injury to podocytes manifests in proteinuria and end-stage kidney disease. Our studies revealed that podocytes undergo epithelial-mesenchymal transition (EMT) during diabetic nephropathy. EMT is a major tissue remodeling processes critical for the development of many embryonic tissues such as the kidney and the vasculature.

Figure legend: Diabetes presented with elevated levels of growth hormone (GH) and for a very long time, it is not known how elevated GH levels contribute proteinuria. Podocytes are specialized cells and enwrap glomerular capillaries, thus contribute glomerular permselectivity and provide ultrafiltration of blood.  Earlier our group discovered the presence of GHR on these podocytes and now we found that excess GH during diabetes exerts its action on the podocytes and elicit aberrant activation of Notch signaling. Activation of Notch signaling results in loss of epithelial features in these podocytes comprises their permselectivity, which eventually results in proteinuria.  

In their recent study, Anil and his colleagues demonstrated that human growth hormone activates Notch signaling and NICD1 expression. Activation of this signaling resulted in podocyte injury and proteinuria in experimental rats. They also showed that patients with diabetic nephropathy display increased NICD1 expression.

Anil K Pasupulati received his M.Sc. (Biochemistry) from Andhra University and Ph.D. from Osmania University. He had post-doctoral experience from the University of Michigan (2008-12). Before moving to the University of Hyderabad in 2014, Anil served at Osmania University and National Institute of Nutrition, Hyderabad. Anil received KV Rao scientific society young scientist Award during his Ph.D. Anil has a longed interest in understanding the molecular and cellular events that trigger secondary complications of diabetes. Earlier, Anil was a recipient of the Wellcome-DBT Early Career Fellowship and DST-INSPIRE Faculty Fellowship.

Source: Nishad R, Mukhi D, Tahaseen SV, Mungamuri SK, Pasupulati AK. Growth hormone induces Notch1 signaling in podocytes and contributes to proteinuria in diabetic nephropathy. J Biol Chem. 2019 Nov 1; 294(44): 16109-16122.

http://www.jbc.org/content/294/44/16109

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