Faculty Collaboration Database

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease. J Am Soc Nephrol 2018 Jul;29(7):1917-1927

Date

05/26/2018

Pubmed ID

29793963

Pubmed Central ID

PMC6050934

DOI

10.1681/ASN.2018030280

Scopus ID

2-s2.0-85049383067 (requires institutional sign-in at Scopus site)   94 Citations

Abstract

Background Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly H₂O₂, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived H₂O₂ contributes to podocyte damage in DKD via elevation of podocyte calcium.Methods We used Dahl salt-sensitive (SS) rats with a null mutation for the Nox4 gene (SS^Nox4-/-) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli.Results Upon induction of type 1 diabetes with streptozotocin, SS^Nox4-/- rats exhibited significantly lower basal intracellular Ca²⁺ levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II-elicited calcium flux was blunted in glomeruli isolated from diabetic SS^Nox4-/- rats compared with that in glomeruli from diabetic SS rats. H₂O₂ stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from Trpc6-knockout mice and, in a similar manner, in podocytes from Trpc5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from Trpc6-knockout or Trpc5/6 double-knockout mice were protected from damage induced by H₂O₂ to the same extent.Conclusions These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.

Author List

Ilatovskaya DV, Blass G, Palygin O, Levchenko V, Pavlov TS, Grzybowski MN, Winsor K, Shuyskiy LS, Geurts AM, Cowley AW Jr, Birnbaumer L, Staruschenko A

Authors

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Calcium
Diabetes Mellitus, Experimental
Diabetic Nephropathies
Hydrogen Peroxide
Male
Mice
Mice, Knockout
NADPH Oxidase 4
Podocytes
Rats
Rats, Inbred Dahl
Reactive Oxygen Species
TRPC Cation Channels
TRPC6 Cation Channel