Podocyte-Specific Regulation of PP2A Worsens Diabetic Kidney Disease (DKD) Progression
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Fang, Zhengying, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Liu, Ruijie, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
We previously showed a critical role of protein phosphatase 2A (PP2A) in regulation of podocyte function and progression of DKD. However, PP2A is ubiquitously expressed with pleiotropic functions, limiting its role of being a DKD therapeutic target. Here, we investigated the role of a podocyte-specific regulatory subunit of PP2A, PPP2R2B in vitro and in vivo in the context of DKD.
By using PHEWAS approach, we screened the variants of genes coding for all PP2A subunits to determine their association with renal outcome in DKD patients. Knock-in (KI) mice with one of the clinical worse outcome-related ppp2r2b missense variants (T202M) was generated, and diabetes was induced with streptozotocin (STZ). Renal function was assessed every two weeks, and all mice were euthanized at the age of 24 weeks for examination.
By PHEWAS study, several variants of ppp2r2b gene were found to be associated with a better or worse renal outcome in DKD patients. Interestingly, single cell transcriptomic data showed that ppp2r2b gene expresses mostly in human podocytes. In vitro study confirmed that ppp2r2b variants correlated with a better or worse clinical outcome led to an increased or decreased PP2A activity, respectively. We generated KI mice with one of the clinical worse outcome-related ppp2r2b missense variants (T202M). In vivo study revealed that diabetic KI mice developed significantly higher level of albuminuria in comparison to diabetic WT mice. Besides, diabetic KI mice also showed worst podocyte injury and loss, and mesangial matrix expansion. As PP2A dephosphorylates p65 NF-κB, we evaluated the phosphorylation level of p65 NF-κB in the glomeruli of these mice. Compared to wildtype mice, KI mice had a higher level of glomerular phosphorylation of p65.
The missense ppp2r2b variants were significantly associated with renal outcome in humans with DKD. KI of one of ppp2r2b missense variants (T202M) resulted in worsened glomerulopathy in diabetic mice. Thus, PPP2R2B, a podocyte-specific PP2A regulatory subunit, could be a better therapeutic target for DKD.
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