# Purinergic control of calcium flux in podocytes

> **NIH VA I01** · CLEMENT J. ZABLOCKI VA MEDICAL CENTER · 2021 · —

## Abstract

The podocyte has become a crucial focus as a target for interventions in kidney disease due to its key role in
regulating glomerular permeability and maintaining glomerular structure. Podocyte injury is believed to be
pathogenetically and prognostically important in diabetic nephropathy (DN). One of the main factors determining
pathological changes of glomerular morphology and permeability are linked to elevation of podocyte intracellular
calcium ([Ca2+]i). Transient receptor potential canonical (TRPC) channels are important players in the
pathogenesis of renal and cardiovascular diseases. ATP is a critical signaling molecule playing key role in
podocyte function. However, our knowledge about purinergic signaling in glomeruli and their regulation of TRPC
channels and [Ca2+]i in podocytes in the setting of DN is rudimentary and therefore is the focus of the current
proposal.
 The central hypothesis of this proposal is that in diabetes significant changes in [Ca2+]i homeostasis in
podocytes occur, which are mediated by: 1) increased concentration of extracellular ATP; 2) remodeling of
purinergic signaling from metabotropic P2Y to ionotropic P2X receptors; 3) excessive production of ROS; and 4)
hyperactivity of TRPC channels; altogether these events lead to glomeruli damage, proteinuria and,
consequently, ESRD. We further hypothesize that increased [Ca2+]i influx in podocytes results in a pathological
increase in glomeruli permeability to albumin. Based on the preliminary data and published findings, the main
objective of this project is to define the specific mechanisms mediating the effect of ATP and ROS on TRPC
channels in freshly isolated glomeruli and to identify the pharmacological targets that control glomerular albumin
permeability in the pathogenesis of DN. To explore this idea, we have developed novel approaches that allow
assessing ATP and H2O2 release with enzymatic biosensors ex vivo and in vivo; measuring endogenous TRPC
channels activity with patch clamp in podocytes of intact glomeruli; quantifying calcium flux in freshly isolated
glomeruli; studying glomerular albumin permeability ex vivo. T2DN and streptozotocin treated Dahl salt-sensitive
rats will be used to test our hypotheses in models of both type 1 and type 2 diabetes. Here we will test the
following Specific Aims: 1) To determine basal and Ang II-induced concentrations of extracellular ATP in diabetic
animals, and to define the effects of ATP on TRPC channels function; 2) To identify the contribution of ROS in
ATP driven signaling pathways; 3) To determine a consequence of altered glomerular permeability in response
to extracellular ATP and TRPC-dependent calcium influx; 4) To define the contributions of specific P2 receptors
by testing the effects of their inhibition on the development of diabetic nephropathy. This research while
fundamental in nature will begin to fill a large gap in knowledge and impact the health and welfare of both the
U.S military personnel and all ben...

## Key facts

- **NIH application ID:** 10047722
- **Project number:** 5I01BX004024-03
- **Recipient organization:** CLEMENT J. ZABLOCKI VA MEDICAL CENTER
- **Principal Investigator:** Alexander Staruschenko
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047722

## Citation

> US National Institutes of Health, RePORTER application 10047722, Purinergic control of calcium flux in podocytes (5I01BX004024-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047722. Licensed CC0.

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