Projects

Role of pericyte angiotensin receptor signaling in kidney disease

Pericytes are an important vascular cell type in the kidney. In addition to supporting endothelial cells in capillaries, they also have specialized functions in the glomerulus, where they are referred to as mesangial cells.

Recent single-cell RNAseq datasets have revealed that pericytes express abundant amounts of the type 1a angiotensin receptor (Figure 1). We hypothesize that this means that pericytes are playing a major role in kidney disease.

Our lab is exploring the role of pericyte angiotensin receptor signaling in kidney disease by conditionally knocking out the angiotensin receptor from pericytes with the Pdgfrb-creERT2 (Figure 2). We are looking at how this affects kidney phenotypes in both Angiotensin II induced hypertension as well as diabetic kidney disease.

This project is supported by the NIDDK (1K01DK121737) AHA (20CDA35320169)

Figure 1 mesangial cell population
Figure 1. Pericytes Express Angiotensin Receptor in the Kidney. A) T-SNE plot of single-cell RNAseq dataset obtained from mouse tissue with different cell populations labeled (Wu et al26). B) Expression of the AT1aR (Gene Name Agtr1a) overlayed onto the t-SNE plot from A. C) Expression of the Pdgfrb overlayed onto the t-SNE plot from A. D) Dot Plot of AT1aR expression in different kidney cell populations. Purple arrow points towards the pericyte population termed mesangial cells.
Figure 2 glomerulus histology GFP vs CD31
Figure 2. Pdgfrβ-CreERT2 Cre Targets Pericytes in the Kidney. Mice were injected with CD31 conjugated to A594 to label the vasculature and crossed to a GFP reporter mouse. Cspg4-creERT2 activity in the Cortex (A) and Medulla (B). Imaging of Pdgfrβ-CreERT2 in the Cortex (C) (arrowhead points to mesangial cells (glomerulus), and arrows point to interstitial pericytes) in medulla (D). Tile Scan of kidney showing extensive Cre activity in pericytes (E).

ACE2

ACE2 is highly expressed in the renal proximal tubule (PT) and endothelial cells. What are the critical pools of ACE2 and how does soluble ACE2 contribute to blood pressure regulation?

Figure 1. ACE2 & Hypertension diagram
1. Is the renal PT a critical cellular source of ACE2? Is soluble ACE2 generated in systemic tissues able to overcome loss of ACE2 from the PT?
2. Is the endothelium a critical source of ACE2? Does shedding from the renal PT affect BP in absence of systemic ACE2?

Pericytes in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in the United States and around the world. In Oregon, it affects thousands of residents making them reliant on renal replacement therapy such as dialysis or kidney transplant. Unfortunately, very few therapies delay the progression of DKD towards ESRD. The major therapeutic strategy to delay progression of DKD is pharmacologic inhibition of the renin angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). Use of these drugs highlights the importance of RAS signaling in the pathophysiology of DKD and also highlights the need for additional therapies to prevent thousands of Oregonians from a debilitating reliance on dialysis or the uncertainty of waiting for kidney transplant.

Our research group has developed a novel mouse model of DKD, combining type 1 diabetes with chronic, low-grade activation of the RAS, which together recapitulates key features of human DKD including alterations to kidney function and kidney structure. This mouse model is an ideal platform for studying the molecular mechanisms that drive DKD and testing out novel therapeutic strategies for preventing and reversing DKD. 

We recently found that a key receptor in the RAS signaling pathway (drug target of ARBs) is abundantly expressed in a specialized cell type of the kidney. Specifically, we found that the type 1 angiotensin receptor (AT1aR) is abundantly expressed within renal mesangial cells. This finding correlates with two well-defined early pathological features of DKD; albuminuria and mesangial expansion. Furthermore, it demonstrates that the cell type with abundant expression of AT1aR is localized to the glomerulus, the anatomical location with characteristic diabetic structural changes to kidney tissue. Taken together, this implicates RAS signaling through mesangial cells as a contributor to the pathophysiology of DKD, however, specific action of AT1aR in mesangial cells has not been examined before.

This project is funded by the Collins Medical Trust.