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Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seq

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posted on 07.07.2021, 17:33 by Yinqiu Wang, Aolei Niu, Yu Pan, Shirong Cao, Andrew S.Terker, Suwan Wang, Xiaofeng Fan, Cynthia L Toth, Marisol A Ramirez Solano, Danielle L Michell, Danielle Contreras, Ryan M Allen, Wanying Zhu, Quanhu Sheng, Agnes B. Fogo, Kasey C Vickers, Ming-Zhi Zhang, Raymond C. Harris
Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single cell-based RNA-seq of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not been previously compared to that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS-/-; db/db mice and compared it to streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS-/- mice utilizing Translating Ribosome Affinity Purification (TRAP) and RNA-seq. Over 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN compared to T1DN. TGF-β signaling pathway genes were upregulated while MAPK pathway genes were downregulated only in T2DN while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number diabetes-induced genes not previously been linked to podocyte injury were confirmed in both mouse and human DN. Differences and similarities in the podocyte translatome in T2DN and T1DN can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury.

Funding

These studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH grants DK51265, DK95785, and DK62794 (to R.C.H. and M.-Z.Z.); NIDDK grant DK103067 (to R.C.H., A.B.F., K.C.V. and M.-Z.Z.) and the Vanderbilt O’Brien Center (NIDDK grant P30DK114809) (to R.C.H. and M.-Z.Z.); U.S. Department of Veterans Affairs VA Merit Award 00507969 (R.C.H.); the Vanderbilt Center for Kidney Disease.

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