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A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease. J Am Soc Nephrol 2018 07;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   13 Citations

Abstract

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 HO, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived HO contributes to podocyte damage in DKD elevation of podocyte calcium. We used Dahl salt-sensitive (SS) rats with a null mutation for the gene (SS) 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. Upon induction of type 1 diabetes with streptozotocin, SS rats exhibited significantly lower basal intracellular Ca 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 rats compared with that in glomeruli from diabetic SS rats. HO stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from 6-knockout mice and, in a similar manner, in podocytes from 5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from 6-knockout or 5/6 double-knockout mice were protected from damage induced by HO to the same extent. 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 Associate Professor in the Physiology department at Medical College of Wisconsin
Oleg Palygin PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Alexander V. Staruschenko 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
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc